Azolobenzazepine derivatives as neurologically active agents

ABSTRACT

The invention relates to azolobenzazepine derivatives of formula (I), wherein: X is O or S; R 1 , R 2 , R 3  and R 4  are independently hydrogen, perfluorolower-alkyl, halogen, nitro or cyano; and C together with the carbon atoms to which it is attached forms a 5-membered aromatic heterocycle selected from the group consisting of a pyrazol and triazole, to pharmaceutical compositions containing them and to methods for the treatment of neurological disorders utilizing them. ##STR1##

This application claims the benefit of U.S. provisional application Pat.No. 60/013,528, filed Mar. 8, 1996.

Which is a National Phase of PCT Application PCT/GB97/00592 filed Mar.4, 1997, priority of which is claimed.

The invention relates to azolobenzazepine derivatives, to pharmaceuticalcompositions containing the same and to the method of use thereof in thetreatment of neuroloical disorders.

More specifically, the invention relates to compounds of the Formula I:##STR2## wherein:

X is O or S;

R¹, R², R³ and R⁴ are independently hydrogen, perfluorolower-alkyl,halogen, nitro is or cyano; and

C together with the carbon atoms to which it is attached forms a5-membered aromatic heterocycle selected from the group consisting of:##STR3## or tautomers thereof, wherein R is cyano, --C(O)OR⁵ (wherein R⁵is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl,cycloalkyl-lower-alkyl, phenyl, phenyl-lower-alkyl,phenyl-lower-alkynyl, lower-alkylthio-lower-alkyl, halo-lower-alkyl,trifluoromethyl-lower-alkyl, lower-alkoxy-lower-alkyl,hydroxy-lower-alkyl, lower-alkylamino, cycloalkylamino, orphenyl-lower-alkylamino), --C(O)NR⁶ R⁷ (wherein R⁶ and R⁷ areindependently hvdrogen, phenyl, phenyl-lower-alkyl,lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl, lower-alkyl,lower-alkoxy, hydroxy, or cycloalkyl, or R⁶ and R⁷ together with thenitrogen atom to which they are attached form a 5- or 6-memberednon-aromatic heterocycle selected from the group consisting ofmorpholinyl, piperidinyl, piperazinyl, pyrrolidinyl andthiomorpholinyl), formyl, phenylcarbonyl, phenyl, lower-alkylcarbonyl,perfluorolower-alkyl, lower-alkoxy-carbonyl-lower-alkyl,carboxy-lower-alkyl, or phenyl-lower-alkylcarbonyl; wherein said phenyl,phenyl-lower-alkyl, phenyl-lower-alkynyl, phenyl-lower-alkyl-amino,phenylcarbonyl or phenyl-lower-alkylcarbonyl groups may optionally besubstituted on the phenyl group thereof by one to three substituents,the same or different, selected from the group consisting oflower-alkyl, lower-alkoxy, halogen, hydroxy and trifluoromethyl;

or a pharmaceutically acceptable acid-addition salt of basic membersthereof; or a pharmaceutically acceptable base-addition salt of acidicmembers thereof; with the proviso that when C together with the carbonatoms to which it is attached forms a triazole ring, at least one of R¹,R², R³ or R⁴ must be other than hydrogen.

The compounds of the Formula I have been found to function asantagonists of the effects which excitatory amino acids, such asglutamate, have upon the NMDA receptor complex and are thus usefull inthe treatment of neurological disorders.

Compounds within the ambit of Formula I above are those wherein:

X, R¹, R², R³, R⁴ and C are as defined above; and

R is cyano, --C(O)OR (wherein R is hydrogen, lower-alkyl, lower-alkenyl,lower-alkynyl, cycloalkyl-lower-alkyl, phenyl, phenyl-lower-alkyl,phenyl-lower-alkynyl, lower-alkylthio- lower-alkyl, halo-lower-alkyl,trifluoromethyl-lower-alkyl, lower-alkylamino, cycloalkylamino, orphenyl-lower-alkyl-amino), --C(O)NR⁶ R⁷ (wherein R⁶ and R⁷ areindependently hydrogen, phenyl, phenyl-lower-alkyl,lower-alkoxy-lower-alkyl, lower-alkyl, lower-alkoxy, hydroxy orcycloalkyl, or R⁶ and R⁷ together with the nitrogen atom to which theyare attached form a morpholinyl group), formyl, phenylcarbonyl, phenyl,lower-alkylcarbonyl, perfluorolower-alkyl,lower-alkoxy-carbonyl-lower-alkyl, or carboxy-lower-alkyl; wherein saidphenyl, phenyl-lower-alkyl, phenyl-lower-alkynyl,phenyl-lower-alkylamino or phenylcarbonyl groups may optionally besubstituted on the phenyl group thereof by one substituent selected fromthe group consisting of lower-alkyl, lower-alkoxy, halogen, hydroxy andtrifluoromethyl.

Other compounds within the ambit of Formula I above are those wherein:

X, R¹, R², R³, R⁴ and C are as defined above: and

R is cyano, --C(O)OR⁵ (wherein R⁵ is hydrogen, lower-alkyl,lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl, phenyl,phenyl-lower-alkyl, phenyl-lower-alkynyl, lower-alkylthio-lower-alkyl,halo-lower-alkyl, trifluoromethyl-lower-alkyl, lower-alkylamino,cycloalkylamino, or phenyl-lower-alkyl amino), --C(O)NR⁶ R⁷ (wherein R⁶and R⁷ are independently hydrogen, phenyl, phenyl-lower-alkyl,lower-alkoxy-lower-alkyl, lower-alkyl, lower-alkoxy, or hydroxy, or R⁶and R⁷ together with the nitrogen atom to which they are attached form amorpholinyl group), formyl, phenylcarbonyl, phenyl,perfluorolower-alkyl, lower-alkoxycarbonyl-lower-alkyl, orcarboxy-lower-alkyl.

Preferred compounds of the formula I above are those wherein R¹, R², R³and R⁴ are independently hydrogen or halogen; and X, C and R are asdefined directly above.

Particularly preferred compounds of the Formula I above are thosewherein:

X and C are as defined directly above;

R¹, R², R³ and R⁴ are independently hydrogen or halogen; and

R is cyano, --C(O)OR⁵ (wherein R⁵ is hydrogen, methyl, ethyl, propyl,isopropyl, butyl, sec-butyl, isobutyl, 2-propenyl, 3-butenyl,1-methyl-3-butenyl, 3-methyl-3-butenyl, 4-pentenyl, 3-butynyl,cyclopropylmethyl, phenyl, phenylmethyl, phenylethyl, phenylpropyl,3-phenyl-2-propynyl, methylthioethyl, methylthiopropyl, chloroethyl,chloropropyl, 2,2,2-trifluoroethyl, isopropylamino, cyclohexylamino,tert-butyl-arnino, phenylmethylamino), --C(O)NR⁶ R⁷ (wherein R⁶ and R⁷are independently hydrogen, phenylmethyl, phenyl, methoxyethyl,ethoxyethyl, propyl, methyl, methoxy, or hydroxy, or R⁶ and R⁷ togetherwith the nitrogen atom to which they are attached form a morpholinylgroup), formyl, phenylcarbonyl, phenyl, trifluoromethyl,tert-butoxy-carbonylmethyl or carboxymethyl.

More particularly preferred compounds of the Formula I above are thosewherein:

One of R¹, R², R³ or R⁴ is chloro and the others are hydrogen: and X, Cand R are as defined directly above.

Preferred species of the invention include:

7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10-(1H,9H)-dione,

7-chloro-3-cyanopyrazolo[3,4-c][1]benzazepine-4,10-(1H,9H)-dione,

7-chloro-3-trifluoromethylpyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,

3-methoxycarbonyl-7-chloropyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,

7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,

3-propoxycarbonyl-7-chloropyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,

7-chloro-3-(2-propenyloxycarbonyl)pyrazolo[3,4c][1]-benzazepine-4,10(1H,9H)-dione,

7-chloro-3-(isopropoxycarbonyl)pyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione,

3-butoxycarbonyl-7-chloropyrazolo[3,4c][1]benzazepine-4,10(1H,9H)-dione,

3-(3-butenyloxycarbonyl)7-chloropyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione,and

3-(3-butynyloxycarbonyl)-7-chloropyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione;or a pharmaceutically acceptable salt thereof.

Another group of compounds within the ambit of Formula I above are thosewherein:

X is O or S;

R¹, R², R³ and R⁴ are independently hydrogen, perfluorolower-alkylhalogen, nitro or cyano; and

C together with the carbon atoms to which it is attached forms a5-membered aromatic heterocycle of the formula: ##STR4## or tautomersthereof, wherein R is cyano, --C(O)OR⁵ (wherein R⁵ is hydrogen,lower-alkyl, lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl,phenyl, phenyl-lower-alkyl, phenyl-lower-alkynyl,lower-alkylthio-lower-alkyl, halo-lower-alkyl,trifluoromethyl-lower-alkyl, lower-alkoxy-lower-alkyl,hydroxy-lower-alkyl, lower-alkylamino, cycloalkylamino, orphenyl-lower-alkylamino), --C(O)NR⁶ R⁷ (wherein R⁶ and R⁷ areindependently hvdrogen, phenyl, phenyl-lower-alkyl,lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl, lower-alkyl,lower-alkoxy, hydroxy, or cycloalkyl, or R⁶ and R⁷ together with thenitrogen atom to which they are attached form a 5- or 6-memberednon-aromatic heterocycle selected from the group consisting ofmorpholinyl, piperidinyl, piperazinyl, pyrrolidinyl andthiomorpholinyl), formyl, phenylcarbonyl, phenyl, lower-alkylcarbonyl,perfluorolower-alkyl, lower-alkoxycarbonyl-lower-alkyl,carboxy-lower-alkyl, or phenyl-lower-alkylcarbonyl; wherein said phenyl,phenyl-lower-alkyl, phenyl-lower-alkynyl, phenyl-lower-alkylamino,phenylcarbonyl or phenyl-lower-alkylcarbonyl groups may optionally besubstituted on the phenyl group thereof by one to three substituents,the same or different, selected from the group consisting oflower-alkyl, lower-alkoxy, halogen, hydroxy and trifluoromethyl.

Another group of compounds within the ambit of Formula I above are thosewherein:

X is O or S;

R¹, R², R³ and R⁴ are independently hydrogen, perfluorolower-alkyl,halogen, nitro or cyano; and

C together with the carbon atoms to which it is attached forms a5-membered aromatic heterocycle of the formula: ##STR5## or tautomersthereof.

Preferred compounds of the Formula I within this latter group are thosewherein R¹, R², R³, R⁴ are independently hydrogen or halogen; and X andC are as defined directly above.

Particularly preferred compounds of the Formula I within this lattergroup are those wherein one of R¹, R², R³ or R⁴ is chloro and the othersare hydrogen, and X and C are defined directly above.

Preferred species within this latter group of compounds of the Formula Iare:

7-chloro-1,2,3-triazolo[4,5-c][1]benzazepine-4,10(1H,9H)-dione;

6-chloro-1,2,3-triazolo[4,5-c][1]benzazepine-4,10(1H,9H)-dione; and

5-chloro-1,2,3-triazolo[4-5-c][1]benzazepine-4,10(1H,9H)-dione;

or a pharmaceutically acceptable salt thereof.

The invention fuirther relates to a method for the treatment ofneurological disorders which comprises administering to a patient inneed of such treatment an effective amount of a compound of the FormulaI ##STR6## wherein:

X is O or S;

R¹, R², R³ and R⁴ are independently hydrogen, perfluorolower-alkyl,halogen, nitro or cyano; and

C together with the carbon atoms to which it is attached forms a5-membered aromatic heterocycle selected from the group consisting of:##STR7## or tautomers thereof, wherein R is cyano, --C(O)OR⁵ (wherein R⁵is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl,cycloalkyl-lower-alkyl, phenyl, phenyl-lower-alkyl,phenyl-lower-alkynyl, lower-alkylthio-lower-alkyl, halo-lower-alkyl,trifluoromethyl-lower-alkyl, lower-alkoxy-lower-alkyl,hydroxy-lower-alkyl, lower-alkylamino, cycloalkylamino, orphenyl-lower-alkylamino), --C(O)NR⁶ R⁷ (wherein R⁶ and R⁷ areindependently hydrogen, phenyl, phenyl-lower-alkyl,lower-alkoxy-lower-alkyl, hydroxylower-alkyl, lower-alkyl, lower-alkoxy,hydroxy, or cycloalkyl, or R⁶ and R⁷ together with the nitrogen atom towhich they are attached form a 5- or 6-membered non-aromatic heterocycleselected from the group consisting of morpholinyl, piperidinyl,piperazinyl, pyrrolidinyl and thiomorpholinyl), formyl, phenylcarbonyl,phenyl, lower-alkylcarbonyl, perfluorolower-alkyl,lower-alkoxy-carbonyl-lower-alkyl, carboxy-lower-alkyl, orphenyl-lower-alkylcarbonyl; wherein said phenyl, phenyl-lower-alkyl,phenyl-lower-alkynyl, phenyl-lower-alkylamino, phenylcarbonyl orphenyl-lower-alkylcarbonyl groups may optionally be substituted on thephenyl group thereof by one to three substituents, the same ordifferent, selected from the group consisting of lower-alkyl,lower-alkoxy, halogen, hydroxy and trifluoromethyl;

or a pharmaceutically acceptable acid-addition salt of basic membersthereof; or a pharmaceutically acceptable base-addition salt of acidicmembers thereof.

The invention further relates to a pharmaceutical composition whichcomprises a compound of the formula I: ##STR8##

wherein:

X is O or S;

R¹, R², R³ and R⁴ are independently hydrogen, perfluorolower-alkyl,halogen, nitro or cyano; and

C together with the carbon atoms to which it is attached forms a5-membered aromatic heterocycle selected from the group consisting of:##STR9## or tautomers thereof, wherein R is cyano, --C(O)OR⁵ (wherein R⁵is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl,cycloalkyl-lower-alkyl, phenyl, phenyl-lower-alkyl,phenyl-lower-alkynyl, lower-alkylthio-lower-alkyl, halo-lower-alkyl,trifluoromethyl-lower-alkyl, lower-alkoxy-lower-alkyl,hydroxy-lower-alkyl, lower-alkylamino, cycloalkylamino, orphenyl-lower-alkylamino), --C(O)NR⁶ R⁷ (wherein R⁶ and R⁷ areindependently hydrogen, phenyl, phenyl-lower-alkyl,lower-alkoxy-lower-alkyl, hydroxy-lower-alkyl, lower-alkyl,lower-alkoxy, hydroxy, or cycloalkyl, or R⁶ and R⁷ together with thenitrogen atom to which they are attached form a 5- or 6-memberednon-aromatic heterocycle selected from the group consisting ofmorpholinyl, piperidinyl, piperazinyl, pyrrolidinyl andthiomorpholinyl), formyl, phenylcarbonyl, phenyl, lower-alkylcarbonyl,perfluorolower-alkyl, lower-alkoxy-carbonyl-lower-alkyl,carboxy-lower-alkyl, or phenyl-lower-alkylcarbonyl; wherein said phenyl,phenyl-lower-alkyl, phenyl-lower-alkynyl, phenyl-lower-alkylamino,phenylcarbonyl or phenyl-lower-alkylcarbonyl groups may optionally besubstituted on the phenyl group thereof by one to three substituents,the same or different, selected from the group consisting oflower-alkyl, lower-alkoxy, halogen, hydroxy and trifluoromethyl;

or a pharmaceutically acceptable acid-addition salt of basic membersthereof; or a pharmaceutically acceptable base-addition salt of acidicmembers thereof; together with a pharmaceutically acceptable carrier,adjuvant, diluent or vehicle; with the proviso that when C together withthe carbon atoms to which it is attached forms a triazole ring, at leastone of R¹, R², R³ or R⁴ must be other than hydrogen.

The invention fuirther relates to a process for preparing a compound ofthe Formula I which comprises:

(I) treating a compound of the Formula II ##STR10## wherein R' islower-alkyl, with an ammonium salt, 2-hydroxypyridine, or a base toprepare a corresponding compound of the formula I wherein C is apyrazole ring; or

(2) treating a compound of the formula XIII ##STR11## wherein R' islower-alkyl, with a base or 2-hydroxypyridine to prepare a correspondingcompound of the formula I wherein C is a triazole ring.

The invention futer relates to the use of a compound of the Formula Ifor the preparation of a medicament for the treatment of neurologicaldisorders.

The term lower-alkyl as used herein means linear or branched hydrocarbonchains having from one to about six carbon atoms and thus includesmethyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, 1-methylbutyl, 3-methylbutyl, n-pentyl, is 1-methylpentyl,1-ethylbutyl, n-hexyl, and the like.

The term perfluorolower-alkyl as used herein means linear or branchedhydrocarbon chains having one to about 4 carbon atoms wherein eachhydrogen atom has been replaced by a fluorine atom and thus includestrifluoromethyl, pentafluoro-ethyl, heptafluoropropyl and the like.

The term halogen, halo, or halide as used herein means chlorine,bromine, iodine and fluorine.

The term lower-alkenyl as used herein means linear or branchedunsaturated hydrocarbon radicals having two to about seven carbon atomsand thus includes ethenyl, 1-propenyl, 2-propenyl, isopropenyl,1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-3-butenyl,3-methyl-3-butenyl, isobutenyl, 4-pentenyl, 3-hexenyl, 5-hexenyl,6-heptenyl and the like.

The term lower-alkynyl as used herein means linear or branchedunsaturated radicals having two to about seven carbon atoms and thusincludes ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl,2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 4-pentynyl, 5-hexynyl,6-heptynyl and the like.

The term cycloalkyl as used herein means C₃ to C₇ saturated monocyclichydrocarbon residues and thus includes cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

The term lower-alkoxy as used herein means linear or branched alkyloxysubstituents having one to about six carbon atoms and thus includesmethoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy,tert-butoxy, 1-methylbutoxy, 3-methylbutoxy, pentyloxy,1-methylpentyloxy, 1-ethylbutoxy, hexyloxy and the like.

Throughout the specification the compounds of the invention will benamed as azolobenzazepine derivatives and will be numbered as shown inthe ring system illustrated hereinbelow. ##STR12##

It will be appreciated that in the compounds of the formula I the5-membered aromatic heterocycles represented by ring C can exist in anumber of tautomeric forms. For example. (a) when C is a pyrazole ringthe compounds of the Formula I can be represented by the formulas Ia andlb and ##STR13## named as pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H) or(2H,9H)-diones, respectively, when X is O, or10-thioxo-pyrazolo[3,4-c][1]benzazepine-4(1H,9H) or (2H,9H)-ones,respectively, when X is S; and (b) when C is a triazole ring thecompounds of the Formula I can be represented by the formulas Ic, Id andIe and named as 1,2,3-triazolo[4,5-c]-[1]benzazepine-4,10(1H,9H),(2H,9H) or (3H,9H)-diones, when X is O, or10-thioxo-1,2,3-triazolo[4,5-c][1]benzazepine-4(1H,9H), (2H,9H) or(3H,9H)-ones wherein X is S. While the compounds of the formula I,wherein C is a pyrazole or triazole ring, will be represented by theformulas Ia and Ic, respectively, throughout the specification, it willbe appreciated that the invention is intended to extend to each of thevarious tautomeric forms (i.e. Formulas Ia-Ie) or to mixtures thereof.##STR14##

The synthesis of the compounds of the Formula I wherein C is a pyrazolering and X is O, may be outlined as shown in Scheme A: ##STR15## Asuitably substituted 4-(2-aminobenzoyl)-1H-pyrazole-5-carboxylate of theformula II, wherein R' is lower-alkyl, preferably ethyl, in anappropriate organic solvent, such as toluene, is treated with about onemole of a base or 2-hydroxypyridine, preferably 2-hydroxypyridine, at atemperature in the range of about room temperature up to the boilingpoint of the solvent used, preferably at the boiling point of thesolvent used, and then the organic solvent is removed and the remainingresidue is heated at a temperature in the range of about 160° C. toabout 170° C. to afford the compounds of the formula I wherein C is apyrazole ring and X is O. Alternatively, the compounds of the formula Iwherein C is a pyrazole ring and X is O can be prepared by treating asuitably substituted compound of the formula II, wherein R' islower-alkyl, preferably ethyl, in an appropriate organic solvent,preferably 1-methyl-2-pyrrolidinone, with at least one mole of anammonium salt, preferably ammonium acetate, at a temperature in therange of about room temperature up to the boiling point of the solventused, preferably at about 160° C.

Alternatively, various compounds of the formula I wherein X is O, C is apyrazole ring and R is --C(O)NR⁶ R⁷ can be prepared as shown in SchemeB. ##STR16## A compound of the formula I wherein X is O, C is a pyrazolering, R is --C(O)OR⁵ and R⁵ lower-alkyl, preferably ethyl, in anappropriate organic solvent, such as toluene, is treated with a molarexcess of a dialkylaluminum-NR⁶ R⁷ reagent (prepared by treating a molarexcess of a trialkylaluminum derivative, preferably trimethylaluminum,in an appropriate organic solvent, preferably toluene, with a molarexcess of an amine of the formula III, HNR⁶ R⁷) at a temperature in therange of about 0° C. up to about room temperature, to afford thecorresponding compounds of the formula I wherein X is O, C is a pyrazolering and R is --C(O)NR⁶ R⁷. Alternatively, a compound of the formula Iwherein X is O, C is ia pyrazole ring, R is --C(O)OR⁵ and R⁵ is hydrogenin an appropriate organic solvent, such as dimethylformamide, can betreated with a molar excess of a coupling agent, preferably1,1'-carbonyldiimidazole, followed by a molar excess of an amine of theformula III, at a temperature in the range of about room temperature upto about 50° C., preferably at about 50° C., to afford the compounds ofthe formula I wherein X is O, C is a pyrazole ring and R is --C(O)NR⁶R⁷.

Alternatively, various compounds of the formula I wherein X is O, C is apyrazole ring, R is --C(O)OR⁵ and R⁵ is other than hydrogen, can beprepared as shown in Schemes C and D. ##STR17## As shown in Scheme C, acompound of the formula I wherein X is O, C is a pyrazole ring, R is--C(O)OR and R⁵ is hydrogen, in an appropriate organic solvent, such asdimethylformamide, is treated with a molar excess of an appropriatecoupling agent, preferably 1,1'-carbonyl-diimidazole, followed by amolar excess of an appropriate compound of the formula IV wherein R⁵ isother than hydrogen, at a temperature in the range of about roomtemperature up to about 70° C., to afford the corresponding compounds ofthe formula I wherein X is O, C is a pyrazole ring, R is --C(O)OR⁵ andR⁵ is other than hydrogen. Alternatively, a compound of the formula Iwherein X is O, C is a pyrazole ring, R is --C(O)OR⁵ and R⁵ is hydrogen,in an appropriate halogenated solvents such as dichloromethanecontaining a few drops of dimethylformamide, is treated with a molarexcess of an activating agent, such as oxalyl chloride, at a temperatureof about room temperature, to afford the compounds of the formula Vwherein X' is halogen, preferably chlorine. The compound of the formulaV can then be treated with an excess of a compound of the formula IVwherein R⁵ is other than hydrogen, at a temperature in the range ofabout room temperature up to about 100° C. preferably at about 100° C.to afford the compounds of the formula I wherein X is O, C is a pyrazolering, R is --C(O)OR⁵ and R⁵ is other than hydrogen. ##STR18## As shownin Scheme D, a suitably substituted compound of the formula I wherein Xis O, C is a pyrazole ring, R is --C(O)OR⁵ and R⁵ is lower-alkyl,preferably ethyl, can be treated with (a) a molar excess of a compoundof the formula IV, wherein R⁵ is other than hydrogen, in the presence ofan acid catalyst, such as hydrochloric acid, at a temperature of aboutroom temperature up to the boiling point of the reaction mixture,preferably at the boiling point of the reaction mixture, (b) with amolar excess of a compound of the formula IV, wherein R⁵ is other thanhydrogen, in the presence of a molar excess of a titanium IVisopropoxide catalyst, at a temperature in the range of about roomtemperature up to the boiling point of the reaction mixture, preferablyat the boiling point of the reaction mixture, or (c) with a molar excessof a compound of the formula IV, wherein R⁵ is other than hydrogen, inthe presence of at least one mole of a distannoxane catalyst, preferably1-hydroxy-3-(isothiocyanato)tetrabutyl distannoxane, in an appropriateorganic solvent, such as toluene, at a temperature in the range of aboutroom temperature up to the boiling point of the reaction mixture,preferably at the boiling point of the reaction mixture, to afford thecorresponding compounds of the formula I wherein X is O, C is a pyrazolering, R is --C(O)OR⁵ and R⁵ is other than (a) hydrogen or (b) the R⁵group which was present in the starting material.

In those instances wherein a compound of the formula I wherein X is O, Cis a pyrazole ring and R is a formyl group is desired, it is preferredto proceed as illustrated in Scheme E. A suitably substituted compoundof the formula I, wherein X is O, C is a pyrazole ring, R is --C(O)NR⁶R⁷ and R⁶ is lower-alkyl and R⁷ is lower-alkoxy, preferably R⁶ is methyland R⁷ is methoxy, in an appropriate organic solvent, such asdimethylformamide, is treated with an excess of an alkylating agent ofthe formula VI, wherein X is a halogen, preferably chlorine, in thepresence of a sodium halide, preferably sodium iodide, and an excess ofan appropriate base, such as sodium carbonate, at a temperature in therange of about 0° C. up to about room temperature, to afford thecompounds of the formula VII. The compound of the formula VII, in anappropriate organic solvent, such as tetrahydrofaran, can then betreated with an appropriate reducing agent, such as ##STR19##diisobutylaluminum hydride (DIBAL™) at a temperature of about -78° C.,to afford the compounds of the formulas VIII and IX. The compounds ofthe formula VIII and IX in an appropriate halogenated organic solvent,such as dichloromethane, can then be treated with excess of anappropriate oxidizing agent, preferably chromium (VI) oxide, in thepresence of an excess of a base, preferably pyridine, at a temperatureof about room temperature, to afford the compounds of the formula X. Thecompounds of the formula X, in an appropriate organic solvent/watermixture, such as acetonitrile/water, can then be treated with an excessof ceric ammonium nitrate, at a temperature of about room temperature,to afford the desired compounds of the formula I wherein X is O, C is apyrazole ring and R is a formyl group.

In those instances wherein a compound of the formula I wherein X is O, Cis a pyrazole ring and R is a lower-alkoxy carbonyl-lower-alkyl group isdesired, it is preferred to proceed as illustrated in Scheme F:##STR20## A suitably substituted 2,5-dioxo-2,5-dihydro-1H-benz[b]azepinederivative of the formula XI, wherein R⁸ is lower-alkyl, in anappropriate alcoholic solvent, such as methanol, is treated with anexcess of hydrazine, at a temperature of about room temperature toafford the desired compounds of the formula XII (compound of Formula Iwherein X is O, C is a pyrazole ring and R is alower-alkoxycarbonyl-lower-alkyl group)

The synthesis of the compounds of the formula I, wherein C is a triazolering and X is O, may be outlined as shown in Scheme G: ##STR21## Asuitably substituted 4-(2-aminobenzoyl)-1H-1,2,3-triazole -5-carboxylateof the formula XIII, wherein R' is lower-alkyl, preferably ethyl, in anappropriate organic solvent, such as tetrahydrofuran, is treated with amolar excess of a base, such as potassium t-butoxide or2-hydroxypyridine, at a temperature in the range of about roomtemperature up to about 170° C., to afford the appropriate triazolederivatives of the formula I.

The compounds of the formula I wherein X is S can be prepared asdescribed in Scheme H: ##STR22## A suitably substituted compound of theformula I wherein X is O, in an appropriate organic solvent, such astoluene, is treated with Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide),preferably 0.5 equivalents, at a temperature of about room temperatureto afford the corresponding compounds of the formula I wherein X is S.

Simple chemical transformations which are conventional and well known tothose skilled in the art of chemistry can be used for effecting changesin the functional groups of the compounds of the formula I to produceother compounds of the formula I. For example, (1) treating acids withammonium acetate in the presence of an appropriate coupling agent, suchas 1,1'-carbonyldiimidazole, to afford the corresponding amide (C(O)NH₂)derivatives, (2) the hydrolysis of esters to afford the correspondingcarboxylic acid derivatives, (3) the treatment of carbamoyl (--C(O)NH₂)groups with a phosphorous oxyhalide, preferably phosphorous oxychloride,to afford the corresponding nitrile (--CN) derivatives, and (4) treatinga carboxylic acid derivative with an activating agent such asphosphorous pentachloride or oxalyl chloride, to afford thecorresponding acid halide and thereafter treating the acid halide withan amine of the formula III (HNR⁶ R⁷) to afford the correspondingcompounds of the formula I which contain a --C(O)NR⁶ R⁷ group.

It will be appreciated that certain compounds of the Formula I canpossess one or more asymmetric carbon atoms and are thus capable ofexisting in a number of stereoisomeric forms, i.e., enantiomeric,diastereomeric and racemic forms. In addition, certain compounds of theFormula I, i.e., those containing a double bond, can exist in, and beisolated in, separate stereoisomeric forms (E and Z) about the doublebond. Additionally, some compounds of the Formula I may also exhibitpolymorphism. Unless otherwise specified herein, the invention isintended to extend to any of the enantiomeric, diastereomeric, racemic,stereoisomeric (E/Z) or polymorphic forms, or to mixtures thereof Thedifferent stereoisomeric forms may be separated one from the other bythe following methods: (a) the separate enantiomers may be synthesizedfrom chiral starting materials or the racemates may be resolved byconventional procedures which are well known in the art of chemistrysuch as chiral chromatography, fractional crystallization ofdiastereomeric salts and the like; and (b) the diastereomers and E/Zstereoisomers can be separated by conventional procedures which are wellknown in the art of chemistry such as chromatography, fractionalcrystallization and the like.

The compounds of Formula I are useful both in the free base form, and inthe form of acid-addition salts, and both forms are within the purviewof the invention. The acid-addition salts are often a more convenientform for use and in practice, use of the salt form inherently amounts touse of the base form. The acids which can be used to prepare theacid-addition salts include preferably those which produce, whencombined with the free base, pharmaceutically-acceptable salts, that is,salts whose anions are relatively innocuous to the animal orzanism inpharmaceutical doses of the salts, so that the beneficial propertiesinherent in the free base are not vitiated by side effects ascribable tothe anions. In practicing the present invention it is convenient to usethe free base form or the hydrochloride, fumarate, toluenesulfonate,methanesulfonate or maleate salts. However, other appropriatepharmaceutically acceptable salts within the scope of the invention arethose derived from other mineral acids and organic acids. Theacid-addition salts of the basic compounds are prepared by standardprocedures well known in the art which include, but are not limitedthereto, dissolving the free base in an aqueous alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and an acid in an organicsolvent, in which case the salt separates directly, or is precipitatedwith a second organic solvent, or can be obtained by concentration ofthe solution. Although medicinally acceptable salts of the basiccompounds are preferred, all acid-addition salts are within the scope ofthe present invention. All acid-addition salts are useful as sources ofthe free base form even if the particular salt per se is desired only asan intermediate product, as, for example, when the salt is formed forpurposes of purification or identification, or when it is used as anintermediate in preparing a medicinally acceptable salt by, for example,ion exchange procedures.

Likewise, the compounds of the Formula I which contain acidic functions,e.g., carboxylic acids, are useful both in the free acid form and in theform of base-addition salts and both forms are within the purview of theinvention. The base-addition salts are often a more convenient form foruse and, in practice, use of the salt form inherently amounts to use ofthe free acid form. The bases which can be used to prepare thebase-addition salts include preferably those which produce, whencombined with the free acids pharmaceutically-acceptable salts, that is,salts whose cations are relatively innocuous to the animal organism inpharmaceutical doses of the salts, so that the beneficial propertiesinherent in the free acid are not vitiated by side effects ascribable tothe cations. The base-addition salts can be prepared by the reaction ofthe free acid with a base, such as alkali metal or ammonium hydroxidesor organic bases such as alkyl, dialkyl, or trialklamines, morpholine,piperidine, or triethanolamine. If desired, the free acids can beregenerated from the base-addition salts by treatment of the salts withan appropriate aqueous acid.

The suitably substituted 4-(2-aminobenzoyl)-1H-pyrazole-5-carboxylatederivatives of the formula II, which are required for the synthesis ofthe compound of the formula I, can be prepared as described in Scheme I.A suitably substituted 4-(2-nitrophenyl)-4-hydroxy-2-butynoate of theformula XIV. ##STR23## wherein R' is lower-alkyl, preferably ethyl, inan appropriate organic solvent, such as diethyl ether ortetrahydrofuran, is treated with at least one mole of a diazo compoundof the formula XV, at a temperature in the range of about roomtemperature up to the boiling point of the reaction mixture, to affordthe 4-(2-nitrophenylhydroxymethyl)-1H-pyrazole-5-carboxylate derivativesof the formula XVI. The compounds of the formula XVI can then be treatedwith a molar excess of an oxidizing agent, such as chromium (VI) oxide,in the presence of a molar excess of a base, preferably pyridine, in ahalogenated solvent such as dichloromethane, at a temperature of aboutroom temperature, to afford the4-(2-nitrobenzoyl)-1H-pyrazole-5-carboxylate derivatives of the formulaXVIII. Alternatively, the compounds of the formula XVIII can be preparedby treating a 4-(2-nitrophenyl)-4-oxo-2-butynoate of the formula XVII,in an appropriate organic solvent, such as tetrahydrofuran with a molarexcess of a diazo compound of the formula XV, at a temperature of aboutroom temperature. The compounds of the formula XVIII can then be treatedwith a molar excess of appropriate reducing agent, such as (1) sodiumhydrosulfite or (2) nickel boride in the presence of an excess of anacid, preferably hydrochloric acid, in an appropriate solvent,preferably ethanol/water when sodium hydrosulfite is used or methanolwhen nickel boride is used, at a temperature in the range of about 0° C.up to the boiling point of the reaction mixture, to afford the compoundsof the formula II.

The suitably substituted compounds of the formula XIII, which arerequired for the synthesis of the compounds of the formula I wherein Cis a triazole ring, can be prepared as described in Scheme J: ##STR24##A suitably substituted 4-(2-nitrophenyl)-4-oxo-2-butynoate of theformula XVII, in an appropriate organic solvent, preferablydimethylformamide, can be treated with a molar excess of sodium azide,at a temperature in the range of about 0° C. up to about roomtemperature, to afford the4-(2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylates of the formula XIX.The compounds of the formula XIX, in an appropriate organic solvent orsolvent mixture, preferably a mixture of ethanol/chloroform, can then behydrogenated at about 50 psi in the presence of a catalyst, preferablyPtO₂, to afford the compounds of the formula XIII.

The suitably substituted compounds of the formulas XIV and XVII, whichare required for the synthesis of the compounds of the formulas II andXIII, can be prepared as shown in Scheme K: ##STR25## A suitablysubstituted aldehyde of the formula XX, in an appropriate organicsolvent, such as tetrahydrofyran, is reacted with a molar excess of analkyne of the formula XXI, wherein R' is lower-alkyl, preferably ethyl,in the presence of a molar excess of a base, preferably n-BuLi, at atemperature in the range of about -78° C. up to about room temperature,preferably at about -78° C., to afford the compounds of the formula XIV.The compounds of the formula XIV, in an appropriate halogenated solvent,such as dichloromethane, can then be treated with a molar excess of anoxidizing agent, such as MnO₂, at a temperature in the range of about 0°C. up to about room temperature, to afford the compounds of the formulaXVII.

The compounds of the formula XI can be prepared by the proceduresdescribed in PCT WO 94/29275, published Dec. 22, 1994, the entirecontents of which are incorporated herein by reference. The compounds ofthe formula III, IV, VI, XV, XX and XXI are either commerciallyavailable, or they can be prepared by procedures known in the art, or bythe procedures described hereinbelow in the examples.

The following examples will further illustrate the invention without,however, limiting it thereto. Unless stated otherwise:

(i) temperatures are given in degrees Celsius (°C.): operations werecarried out at room or ambient temperature, that is, at a temperature inthe range of 18-25° C.;

(ii) evaporation of solvent was carried out using a rotate evaporatorunder reduced pressure (600-4000 pascals; 4.5-30 mm Hg) with a bathtemperature of up to 60° C.;

(iii) flash chromatography was carried out on 40 μm silica gel flashchromatography packing obtained from J. T. Baker; thin layerchromatography (TLC) was carried out on Analtech 0.25 mm silica gel GHLFplates (Art 21521), obtainable from Analtech, Newark, Del., USA;

(iv) the course of the reactions and the identity and homogenity of theproducts were assessed by one or more of thin layer chromatography(TLC), high pressure liquid chromatography (HPLC), or gas-liquidchromatography (GLC),

(v) melting points are uncorrected and (dec) indicates decomposition;the melting points given are those obtained for the materials preparedas described; polymorphism may result in isolation of materials withdifferent melting points in some preparations;

(vi) the structures of the compounds of the invention were establishedby the mode of synthesis, and by one or more of micro analytical(elemental analysis) data, infrared, or nuclear magnetic resonance (NMR)spectroscopy, or mass spectrometry;

(vii) yields and reaction times are given for illustration only;

(viii) reduced pressures are given as absolute pressures in Pascals(pa); other pressures are given as gauge pressures in bars;

(ix) chemical symbols have their usual meanings; the followingabbreviations have also been used: v (volume), w (weight); mp (meltingpoint), L [liter(s)], mL (milliliters), mmol (millimoles), g [gram(s)],mg [milligram(s)], min. [minute(s)], hr. [hour(s)];

(x) solvent ratios are given in volume:volume (v/v) terms, unlessindicated otherwise;

(xi) unless otherwise specified, reactions were run under an atmosphereof nitrogen (N₂); and

(xii) the term continuous chromatography refers to the followingprocess: A single-neck round bottom flask is charged with solvent (halfto two-thirds full) and equipped with a pressure-equalizing additionfunnel which is topped with a reflux condenser. A plug of glass wool isinserted into the addition funnel just above the stopcock and silica gelis added to the addition funnel until it is half to two-thirds full. Thestopcock is opened, a solution of the compound is applied to the top ofthe silica gel and the apparatus is purged with nitrogen. The solvent inthe flask is heated so that it refluxes into the condenser and dripsonto the top of the silica gel, passing through the silica gel and backinto the round bottom flask. The progress of the purification can bemonitored by tlc of the solution in the flask. Fractions can be obtainedor solvent changed simply by switching flasks.

EXAMPLE 1 (a) Ethyl 4-(4-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate

To a cooled (-78° C.) solution of ethyl propiolate (8.96 mL, 88.4 mmol)in THF (100 mL) was added n-butyllithium (37.5 mL of 2.37M solution inhexane, 88.9 mmol) dropwise over 70 minutes so as to maintain theinternal temperature below -70° C. Additional THF (5 mL) was used torinse the addition funnel. A solution of 4-chloro-2-nitrobenzaldehyde(14.88 g, 80.2 mmol) in THF (30 mL) was transferred to the additionfiunel and added dropwise is over 47 minutes to maintain the reactiontemperature below -70° C. Additional THF (5 mL) was used to rinse theaddition funnel. The solution was stirred for 90 minutes at -70° C. andwas then warmed to -60° C. glacial acetic acid (18.3 mL, 316 mmol) wasquickly added. The solution was allowed to warm to 10° C. over 60minutes and poured into diethyl ether (900 mL). The resulting solutionwas washed with saturated aqueous sodium carbonate (2×450 mL) andsaturated aqueous sodium chloride (1×450 mL). The organic layer wasdried over anhydrous sodium sulfate, filtered, and concentrated on arotary evaporator. This product was purified by flash chromatographyeluting with ethyl acetate:hexanes (90:10) to give the title compound asred oil (14.73 g, 64.8%).

The 4-chloro-2-nitrobenzaldehyde starting material can be prepared asfollows: Borane dimethylsulfide (156 mL, 1.55 moles) was added to astirred solution of 4-chloro-2-nitro-benzoic acid (313.0 g, 1.55 moles)and dry tetrahydrofiuran (2 L) at room temperature under N₂ until about30 mL had been added. The reaction mixture was then heated to gentlereflux. The rest of the borane dimethylsulfide was added dropwise (3mL/min) with heating to maintain the temperature at gentle reflux.Heating at reflux was continued for 2.5 hours after addition wascompleted. Additional borane dimethylsulfide (20 mL, 0.2 mole) was addedto the reaction mixture and heating was continued for 10 minutes. Thereaction mixture was allowed to cool to room temperature and thereaction mixture was concentrated under water aspirator vacuum. Theresidue was dried under vacuum, then was dissolved in methylene chloride(1.7 L) and the solution was added (15 minutes) to a stirred mixture ofpyridinium chlorochromate (375 g, 1.74 moles) and methylene chloride (3L) under N₂. Stirring was continued at room temperature for 0.5 hours,then the reaction mixture was heated at reflux for 1.5 hours. Additionalpyridinium chlorochromate (110 g, 0.51 mole) was added and heating atreflux was continued for 1.5 hours. The reaction mixture was allowed tocool to room temperature and diethyl ether (3 L) was added withstirring. The mixture with filtered through CELITE™ and the pad wasflushed with diethyl ether (2×500 mL). The filtrate and wash liquorswere combined and filtered twice through silica gel (1200 mL) and (1200mL). The filtrate was concentrated under water aspirator vacuum. Theresidue was dried under vacuum to give 4-chloro-2-nitro-benzaldehyde asa yellow powder (247.32 g, 86%).

(b) Diethyl4-[(4-chloro-2-nitrophenyl)hydroxymethyl]-1H-pyrazole-3,5-dicarboxylate

A solution of ethyl 4-(4-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate(5.00 g, 17.7 mmol) and ethyl diazoacetate (2.75 g, 26.5 mmol) indiethyl ether (43.3 mL) was refluxed for 5 days. After cooling to roomtemperature the reaction mixture was chromatographed eluting with ethylacetate:hexanes (20:80, 30:70, 40:60, and 50:50). All of the fractionscontaining the desired compound were combined, concentrated on therotary evaporator, and the product was recrystallized twice from toluene(total volume 225 mL) to give the title compound as a white solid (4.15g, 59%, mp 60° C.).

Alternatively, the title compound can be prepared as follows:

A mixture of ethyl 4-(4-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate (253g, 0.89 mole), ethyl diazoacetate (102 g, 0.89 mole) and drytetrahydrofuran (1.4 L) was heated at reflux with stirring under N₂ for3 days. Additional ethyl diazoacetate (40.0 g, 0.35 mole) was added andheating at reflux was continued for 18 hours. The solvent was removedunder water aspirator vacuum. The residue (409 g) was dissolved intoluene (800 mL) and hexane (800 mL) was slowly added to the solutionand the resultant mixture was stirred for 1 hour. The mixture wasfiltered. The filter cake was washed with hexane (1 L) and dried to givea tan-yellow powder (216.4 g) This tan-yellow powder was dissolved inhot toluene (1.0 L) and hexane (1 L) was added dropwise to the warmstirred solution. The stirring mixture was allowed to cool to roomtemperature while stirring overnight. The mixture was filtered. Thefilter cake was washed with hexane (2×500 mL) and dried at 50° C. undervacuum to give the title compound as an off-white powder (202.55 g,57%). The above filtrate was concentrated under water aspirator vacuum.The residue (123 g) was placed on a silica gel (5 L) column and flasheluted with methylene chloride:methanol, 99.5:0.5 to 98:2, to giveadditional title compound as an off-white powder (9.85 g, 2.78%).

(c) Diethyl 4-(4-chloro-2-nitrobenzoyl)-1H-pyrazole-3,5-dicarboxylate

Chromium (VI) oxide (17.48 g, 174.8 mmol) was added over 37 minutes to asolution of pyridine (27.6 mL, 349.5 mmol) in dichloromethane (400 mL).Diethyl4-[(4-chloro-2-nitro-phenyl)hydroxymethyl]-1H-pyrazole-3,5-dicarboxylate(11.56 g, 29.1 mmol) was added as a solid over 9 minutes. The reactionmixture was allowed to stir at room temperature 44 is hours. Thesolution was filtered and the organic layer was washed with aqueoushydrochloric acid (500 mL, 3N). The aqueous layer was extracted withethyl acetate (3×250 mL) and dichloromethane (3×250 mL). The resultingorganic extracts were combined and concentrated on the rotary evaporatorto give a crude solid (10.92 g). The product was purified bychromatography eluting with dichloromethane:2-propanol (98:2, 96:4, and94:6). The desired product was obtained from the mixed fractions byrecrystallization from toluene (250 mL). Clean fractions fromchromatography were combined with recrystallized product to give thetitle compound as a white solid (9.85 g, 86%, mp 168° C.).

Alternatively, the title compound can be prepared as follows:

Pyridine (481.6 g, 6.08 moles) was added dropwise over 35 minutes to amechanically stirred suspension of chromium (VI) oxide (304.56 g, 3.05moles) (WARNING: adding pyridine to chromium (VI) oxide is an extremelydangerous procedure and, therefore, chromium (VI) oxide shouldpreferably be added to pyridine) and methylene chloride (6 L) under N₂.The reaction as stirred for 40 minutes after pyridine addition wascompleted and then a solution of diethyl 4-[(4-chloro-2-nitrophenyl)hydroxymethyl]-1H-pyrazole-3,5-dicarboxylate (202.5 g, 0.507mole) in methylene chloride (1.3 L) was added dropwise over 0.5 hours atroom temperature. Stirring at room temperature was continued overnight.CELITE™ (205 g) and additional Collins reagent [chromium (VI) oxide (50g, 0.5 mole) and pyridine (120.3 g, 1.52 moles, methylene chloride (1L)] were added and the reaction mixture was stirred for 4 days. Thereaction mixture was filtered. The filter cake was washed with methylenechloride (3 L) and filtered. The filtrate and wash liquors were combinedand concentrated under water aspirator vacuum. The residue was dissolvedin ethyl acetate(2 L) and this solution was filtered through a shortcolumn of silica gel (3 L). The filtrate was concentrated under wateraspirator vacuum. The solid residue was dissolved in warm toluene (800mL) and then hexane (800 mL) was added with stirring. The mixture wasallowed to cool to room temperature and was then filtered. The filtercake was washed with hexane (2×500 mL), and dried under vacuum at 50° C.to give the title compound as a white powder (186.08 g, 93%).

(d) Diethyl 4-(4-chloro-2-aminobenzoyl)-1H-pyrazole-3,5-dicarboxylate

To absolute ethanol (265 mL) was added diethyl4-(4-chloro-2-nitrobenzoyl)-1H-pyrazole-3,5-dicarboxylate (8.7 g, 22.25mole). The mixture was stirred 20 minutes and then was slowly heated toreflux. A solution of sodium hydrosulfite (15.29 g, 87.86 mmol) in water(85.5 mL) was added in portions over 4 hours. The solution was refluxed4 days. The mixture was allowed to cool and the solid was filtered off.The organic laver was concentrated on a rotary evaporator to give ayellow solid (18.23 g). This crude product was purified by flashchromatography eluting with ethyl acetate:hexanes (15:85, 25:75, 30:70)to give a yellow solid (3 g). The mixed fractions containing theinorganic material and product were concentrated on a rotary evaporatorand the product was continuously chromatographed eluting withchloroform:2-propanol (98:2). The product was concentrated on a rotaryevaporator and combined with clean fractions from the first column togive the title compound as a yellow solid (combined weight 5.2 g, 64%,mp 201° C.).

Alternatively, the title compound can be prepared as follows: A mixtureof nickel acetate (444 g, 1.78 moles) and water (6.6 L) was cooled to 8°C. with stirring under nitrogen: then a solution of sodium borohydride(271 g, 7.16 moles) in water (3.55 L) was added dropwise over 1.5 hoursmaintaining the reaction temperature between 8° C. and 12° C. Thereaction mixture was then stirred for 1.5 hours at 8-12° C. The reactionmixture was filtered through a coarse scintered glass filter funnel,keeping, the black filter cake wet (Caution: this black powder may bepyrophoric if allowed to dry). The filter cake was washed first withwater (6×2 L), then with ethanol (2×2 L) and finally with methanol (1L). The methanol wet filter cake (Ni₂ B, pyrophoric) was transferred toa 22 L flask with methanol (8 L). A solution of diethyl4-(4-chloro-2-nitrobenzoyl)-1H-pyrazole-3,5-dicarboxylate (111.0 g, 0.28mole) in hydrochloric acid (2.52 L) was added. The reaction mixture washeated to 64° C. and was kept at 64° C. for 6 hours; then was allowed tocool to room temperature and was filtered through CELITE™. The CELITE™layer was washed with methanol (2×2 L). The filtrate and wash liquorswere combined and the methanol was distilled off under water aspiratorvacuum. Water (1 L) was added to the reaction and the mixture wasfiltered. The filter cake was washed with water (2×500 mL) and driedunder vacuum at 40° C. to give the title compound as a yellowish solid(98.81 g, 96%).

(e)7-Chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10-(1H,9H)dione

To a solution of 2-hydroxypyridine (1.30 g, 13.69 mmol) in toluene (400mL) was added diethyl4-(4-chloro-2-amino-benzoyl)-1H-pyrazole-3,5-dicarboxylate (5 g, 13.69mmol). The mixture was refluxed for 2 days and then the solvent wasdistilled off and the residual solid was heated at 171-172° C. for 4days. The solid was allowed to cool and was continuously chromatographedeluting for 2 hours with dichloromethane to remove starting material.The remaining material on the column was eluted withchloroform:2-propanol (97:3) for 4 days. After each day the solvent inthe receiving flask was replaced with fresh solvent. Filtering thesolvent from the first two receiving flasks gave the title compound as awhite solid (1.65 g, 38%, mp 290° C.). Alternatively, the title compoundcan preferably be removed from the column by elution withethanol/chloroform (7:93).

Alternatively, the title compound can be prepared as follows: A mixtureof diethyl 4-(4-chloro-2-aminobenzoyl)-1H-pyrazole-3,5-dicarboxylate(133.64 g, 0.365 mole), ammonium acetate (2.82 g, 0.0365 mole), and1-methyl-2-pyrrolidinone (267 mL) was heated with stirring at 160° C.under N₂ for 14 hours. After cooling to room temperature, the reactionmixture was poured into water (4 L) with stirring. Stirring wascontinued for 0.5 hours, then the mixture was filtered. The filter cakewas suspended in water (3 L), stirred for 0.5 hours and filtered. Thefilter cake was washed with water (3×600 mL) and dried under vacuum togive an off-white powder (110.3 g). This product was washed withmethylene chloride (1 L) and dried under vacuum to give an off-whitepowder (105.23 g). This sample was recrystallized from glacial aceticacid and filtered. The filter cake was washed with water and dried undervacuum at 50° C. to give the title compound as a white powder (67.7 g,59%).

EXAMPLE 27-Chloro-3-[(2-methoxyethyl)carbamoyl]pyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione

To a solution of trimethylaluminum in toluene (5.34 mL, 10.7 mmol) wasadded 2-methoxyethylamine (0.93 mL, 10.7 mmol) and the solution wasstirred for 0.5 hours. A portion (0.63 mL) of this solution was added toa solution of7-chloro-3-(ethoxycarbonyl)pyrazolo-[3,4-c][1]benzazepine-4,10(1H,9H)-dione(171 mg, 0.534 mmol) in toluene (1.3 mL). The resulting solution wasstirred 4.5 hours at room temperature and then was quenched by theaddition of aqueous hydrochloric acid (1.6 mL, 1N) and water (50 mL).The layers were separated and the aqueous layer was extracted with ethylacetate (5×30 mL) and methylene chloride (5×30 mL). The combinedorganics were concentrated on a rotary evaporator to yield a crude solid(70 mg). The aqueous layer was diluted with water (300 mL) andcontinuously extracted with chloroform (250 mL) for 64 hours. Thechloroform was concentrated on a rotary evaporator to yield a solid (60mg). Both solids were combined and purified by flash chromatographyeluting with methylene chloride:2-propanol (95:5, 90:10, 80:20) to givethe title compound, (41% yield, m.p. 287-291° C.). Alternatively, thetitle compound can preferably be removed from the column by elution withethanol:chloroform (7:93).

EXAMPLE 37-Chloro-3-(dipropylcarbamoyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

To a solution of trimethylaluminum in toluene (4.68 mL 9.38 mmol) wasadded dipropylamine (1.29 mL, 9.38 mmol) and the solution was stirredfor 45 hours. A portion (1.9 30 mL) of this solution was added to asolution of7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione(500 mg, 1.56 mmol) in toluene (2 mL). Additional toluene (7 mL) wasadded. The solution was stirred for 70 minutes at room temperature andthen quenched with 1N hydrochloric acid (9.3 mL). The layers wereseparated and the aqueous layer was extracted with ethyl acetate (3×50mL). The combined organics were washed with 1N hydrochloric acid andwater (25 mL) and concentrated by rotary evaporation. The crude residuewas purified by chromatography eluting with hexanes:ethyl acetate(95:5-50:50) to give the title compound (31% yield, m.p. 270° C.).

EXAMPLE 47-Chloro-3-(N-benzylcarbamoyl)pyrazolo[3,4-c[1]benzazepine-4,10(1H,9H)-dione

Benzylamine (1.34 mL, 12.5 mmol) was added to a solution oftrimethylaluminum in toluene (6.25 mL, 12.5 mmol) and the solution wasstirred for 30 minutes. A portion (759 μL) of the resulting solution wasadded to a solution of7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione(200 mg, 0.625 mmol) in toluene (1.56 mL). The resulting solution wasstirred 48 hours at room temperature and then quenched with aqueoushydrochloric acid (1.88 mL, 1N) and water (30 mL). The aqueous layerphase was extracted with dichloromethane (5×25 mL). The organic layerswere combined and the insoluble material was filtered and dried to givethe title compound (203 mg, 85% yield, m.p. 335-336° C.).

EXAMPLE 57-Chloro-3-(morpholinocarbonyl)pyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione

Morpholine (268 μL, 3.06 mmol) was added to a solution oftrimethylaluminum in toluene (1.56 mL, 3.13 mmol) and the solution wasstirred for 20 minutes. A portion (365 μL) of the resulting solution wasadded to a solution of7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione(100 mg, 0.313 mmol) in toluene (0.760 mL). The resulting solution wasstirred for 4 hours at room temperature and then quenched with aqueoushydrochloric acid (1.88 mL, 1N) and water (50 mL). The aqueous layer wasextracted with chloroforrn (7×50 mL) and ethyl acetate (3×50 mL). Thecombined organic layers were concentrated on a rotary evaporator. Thecrude product was purified by flash chromatography eluting withchloroform:2-propanol (99:1-80:20) to give the title compound (89.9 mg,80% yield, m.p. 347° C.).

EXAMPLE 67-Chloro-3-[N,N-bis-(2-ethoxyethyl)carbamoyl]pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

Bis-(2-ethoxyethyl)amine (560 μL, 3.13 mmol) was added to a solution oftrimethylaluminum in toluene (1.56 mL, 3.13 mmol) and the solution wasstirred for 20 minutes. A portion (424 μL) of the resulting solution wasadded to a solution of7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione(100 mg, 0.313 mmol) in toluene (780 μL). The resulting solution wasstirred for 4.5 hours at room temperature and then quenched with aqueoushydrochloric acid (1.5 mL, 1N) and water (20 mL). The aqueous layer wasextracted with ethyl acetate (3×50 mL) and the organic layers wereconcentrated on a rotary evaporator. The crude product was purified byflash chromatography eluting with chloroform:2-propanol (99:1-80:20) togive the title compound (60.8 mg, 45% yield, m.p. 202° C.).

EXAMPLE 77-Chloro-3-[N,N-bis-(2-methoxyethyl)carbamoyl]pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

Bis-(2-methoxyethyl)amine (560 μL, 3.13 mmol) was added to a solution oftrimethylaluminum in toluene (1.56 mL, 3.13 mmol) and the solution wasstirred for 20 minutes. A portion (403 μL) of the resulting solution wasadded to a solution of7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c[1]benzazepine-4,10(1H,9H)-dione(100 mg, 0.313 mmol) in toluene (780 μL). The resulting solution wasstirred for 24 hours at room temperature and then quenched with anaqueous hydrochloric acid solution (1.8 mL, 1N) and water (15 mL). Theaqueous layer was extracted with chloroform (7×25 mL). The organiclayers were combined and concentrated on a rotary evaporator. The crudeproduct was purified by flash chromatography eluting withchloroform:2-propanol (99:1-95:5) to give the title compound (421 mg,67% yield, m.p. 207-209° C.).

EXAMPLE 87-Chloro-3-[(N-methoxy-N-methylamino)carbonyl)]pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

To N,O-dimethylhydroxylamine hydrochloride (550 mg, 5.6 mmol) was addedtrimethylaluminum in toluene (2.8 mL, 5.6 mmol) and the solution wasstirred for 15 minutes at 0° C. A portion (1.5 mL) ofthe resultingsolution was added to a solution of7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione(300 mg, 0.938 mmol) in toluene (5 mL) at 0° C. The resulting solutionwas allowed to warm to room temperature and was stirred for 4 hours. Thesolution was quenched with aqueous hydrochloric acid (8.4 mL, 1N) andwater (50 mL). The aqueous layer was extracted with dichloromethane(8×30 mL) and the organic layers were concentrated by rotary evaporationto give a solid (160 mg). The aqueous layer phase was then continuouslychromatographed with dichloromethane for 19 hours. The organic layer wasconcentrated by rotary evaporation to give a solid (190 mg). The twosolids were combined and purified by flash chromatography eluting withdichloromethane:2-propanol (100% dichloromethane to 90:10). Thefractions collected were combined and concentrated by rotary evaporationto give the title compound (220 mg, 70% yield, m.p. 287° C.).

EXAMPLE 97-Chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10-(1H,9H)-dione

A solution of7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione(6 g, 18.75 mmol) in aqueous sodium hydroxide (206 mL, 0.2N) wasrefluxed for 135 minutes. The mixture was cooled to room temperature andglacial acetic acid (30 mL) was added. The insoluble material wasfiltered and dried to give the title compound as a yellow solid (5.1 g,94%, m.p. >400° C. dec.).

EXAMPLE 107-Chloro-3-[[(tert-butylamino)oxy]carbonyl]pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

A solution of7-chloro-3-(carboxy)pyrazolo[3,4-cl[1]-benzazepine-4,10(1H,9H)-dione(400 mg, 1.37 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole(334 mg, 2.06 mmol) in N,N-dimethylformamide (16 mL) was stirred for 1hour. In one portion, N-tert-butylhydroxylamine hydrochloride (516 mg,4.11 mmol) was added and the solution was stirred for 17 hours at roomtemperature. To the resulting solution was added water (20 mL). Theinsoluble material was filtered and washed with hot methanol (3×20 mL)to give the title compound (300 mg, 61% yield, m.p. 258° C.).

EXAMPLE 117-Chloro-3-[[(cyclohexylamino)oxy]carbonyl]pyrazolo[3,4-c][1]-benzazepine-4,10(1H,9H)-dione

A solution of7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (300mg, 1.03 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (251mg, 1.55 mmol) in N,N-dimethylformamide (12 mL) was stirred for 1 hour.In one portion N-cyclohexylhydroxylamine hydrochloride (469 mg, 3.09mmol) was added and the solution was stirred for 2 hours at roomtemperature. To the resulting solution was added water (15 mL). Theinsoluble material was filtered and dried to give the title compound(286 mg, 72% yield, m.p. 220° C.).

EXAMPLE 127-Chloro-3-[[(isopropylamino)oxy]carbonyl]pyrazolo[3,4-c]-[1]benzazepine-4,10(1H,9H)-dione

A solution of7-chloro-3-(carboxy)pyrazolo[3,4-][1]benzazepine-4,10(1H,9H)-dione (300mg, 1.03 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (251mg, 1.55 mmol) in N,N-dimethylformamide (12 mL) was stirred for 1 hour.In one portion N-isopropylhydroxylamine hydrochloride (345 mg, 3.09mmol) was added and the solution was stirred for 55 minutes at roomtemperature. To the resulting solution was added water (40 mL) giving aprecipitate which was separated bv filtration. This crude product waspurified by flash chromatography eluting with chloroform:2-propanol(98:2-96.5:3.5) to give the title compound (167 mg, 47% yield, m.p. 224°C.).

EXAMPLE 137-Chloro-3-[[(benzylamino)oxy]carbonyl]pyrazolo[3,4-c]-[1]benzazepine-4,10(1H,9H)-dione

A solution of7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (100mg, 0.344 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole(83.5 mg, 0.515 mmol) in N,N-dimethylformamide (1.4 mL) was stirred for1 hour. In a separate flask was placed N-benzylhydroxylaminehydrochloride (82.2 mg, 0.515 mmol), triethylamine (71.7 μL, 0.515mmol), and N,N-dimethylformamide (2 mL). This solution was stirred for20 minutes. The hydroxylamine solution was added to the acylimidazolesolution and the resulting solution was stirred for 1 hour at 70° C. Thesolution was cooled to room temperature and water (10 mL) was added. Theinsoluble material was filtered and dried to give the title compound(110 mg, 81% yield, m.p. 169-179° C. dec.).

EXAMPLE 147-Chloro-3-(aminocarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

A solution of7-chloro-3-(carboxy)pyrazolo[3,4c][1]-benzazepine-4,10-(1H,9H)-dione (1g, 3.44 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (0.64mg, 3.95 mmol) in N,N-dimethylformamide (25 mL) was stirred for 64.5hours. In one portion, ammonium acetate (0.796 mg, 10.33 mmol) wasadded, followed by additional N,N-dimethylformamide (15 mL). Thesolution was stirred for 3.75 hours at room temperature and concentratedin vacuo for 45 minutes. The residue was washed with water (3×20 mL).The insoluble material was filtered and dried to give the title compound(967 mg, 97% yield, m.p. 224-225° C.).

EXAMPLE 157-Chloro-3-(phenyloxycarbonyl)pyrazolo3,4-c][1]benzazepine-4,10(1H,9H)-dione

A solution of7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500mg, 1.72 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (418mg, 2.58 mmol) in N,N-dimethylformamide (7 mL) was stirred for 16.75hours. In one portion, phenol (486 mg, 5.16 mmol) was added and thesolution was stirred for 24 hours at 70° C. To the resulting solutionwas added water (30 mL), giving a precipitate which was separated byfiltration. This crude product was purified by chromatography elutingwith chloroform:2-propanol (98:2-90:10) to give the title compound (330mg, 53% yield, m.p. 265° C.).

EXAMPLE 167-Chloro-3-(benzyloxycarbonyl)pyrazolo[3,4-c[1benzazepine-4,10(1H,9H)-dione

A solution of7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500mg, 1.72 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (418mg, 2.58 mmol) in N,N-dimethylformamide (7 mL) was stirred 13 minutes.In one portion benzyl alcohol (534 μL, 5.16 mmol) was added. Thesolution was stirred for 17.5 hours at room temperature and 2.75 minutesat 55° C. The solution was allowed to cool to room temperature and water(10 mL) was added. The insoluble material was filtered and dried to givethe title compound (360 mg, 55% yield, m.p. 254° C.).

EXAMPLE 177-Chloro-3-(2-propenyloxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

To a solution of7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (500mg, 1.7 mmol) (compound of Example 9) in dichloromethane (15 mL) wasadded N,N-dimethylformamide (2 drops) and then in one portion oxalylchloride (300 μL, 3.4 mmol). The resulting solution was stirred for 24hours at room temperature, concentrated by rotary evaporation, and allylalcohol (15 mL) was added to the residue. The mixture was heated at 100°C. for 15 minutes and concentrated by rotary evaporation. The residuewas purified by flash chromatography eluting withdichloromethane:methanol (95:5) to give the title compound as a solid(358 mg, 63% yield. 247-249° C.).

EXAMPLE 187-Chloro-3-(isopropoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

A solution of7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione(500 mg, 1.56 mmol), 2-propanol (60 mL), and concentrated hydrochloricacid (3 drops) was subjected to three cycles of partial solvent removalby slow distillation (over 6 hours) followed by overnight reflux. Afterthe third cycle, solvent was removed by rotary evaporation and the crudeproduct was purified by flash chromatography eluting withdichloromethane:2-propanol (95:5-85:15) to yield the title compound as awhite solid (256 mg, 48%, m.p. 291° C). Alternatively, the titlecompound can be prepared as described in Example 18 shown hereinbelow inTable 1.

EXAMPLE 197-Chloro-3-cyanopyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

A solution of7-chloro-3-(aminocarbonyl)pyrazolo[3,4-c[1]benzazepine-4,10(1H,9H)-dione(590 mg, 2.03 mmol) (compound of Example 14) in phosphorous oxychloride(2.56 mL) was refluxed for 70 minutes. The excess phosphorousoxychloride was distilled off at atmospheric pressure and 106° C. To theremaining dark brown residue was added water (40 mL). The aqueous phasewas extracted with ethyl acetate (4×50 mL). The organic layers werecombined and dried over magnesium sulfate, filtered, and concentrated ona rotary evaporator to give the title compound as a broaqvgold solid(≈216 mg, 39% yield, m.p. 370° C. dec.).

EXAMPLE 20 (a)1-(4-Methoxyphenylmethyl)-7-chloro-3-[(N-methoxy-N-methyl-amino)carbonyl]pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dioneor2-(4-Methoxyphenylmethyl)-7-chloro-3-[(N-methoxy-N-methylamino)carbonyl]-pyrazolo[3,4-c][1]benzazepine-4,10-(2H,9H)-dione

To a solution of7-chloro-3-[(N-methoxy-N-methylamino)carbonyl]pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione(1.7 g, 5.07 mmol) (compound of Example 8) at 0° C. was addedN,N-dimethylformamide (25 mL) and sodium iodide (154 mg, 1.03 mmol). Thesolution was stirred at 0° C. for 10 minutes and sodium carbonate (639mg, 6.03 mmol) and ethanol (17 μL) were added. The solution was stirredfor 15 minutes and 4-methoxybenzyl chloride (811 mg, 5.18 mmol) wasadded. The solution was stirred at room temperature for 16 hours. Thesolution was quenched with saturated ammonium chloride (84 mL) andexhaustively extracted with ethyl acetate (10×40 mL). The organic layerswere combined, dried over sodium sulfate, filtered, and concentrated byrotary evaporation to give a yellow oily solid. The crude material waspurified by flash chromatography eluting with cyclohexane:ethyl acetate(90:10-70:30) to give one of the title compound regioisomers cleanly (1g, 44%); R_(f) 0.51 (1:1 ethyl acetate:hexane).

EXAMPLE 20 (b)1-(4-Methoxyphenylmethyl)-7-chloro-3-formylpyrazolo3,4c][1]benzepine-4,10(1H,9H)-dioneor2-(4-methoxyphenylmethyl)-7-chloro-3-formylpyrazolo[3,4-c[1]benzazepine-4,10(2H,9H)-dione

A solution of the single regioisomer from Example 20(a) above (955 mg,2.10 mmol) in THF (48 mL) was cooled to -78° C. and diisobutylaluminumhydride in dichloromethane (14.7 mL, 14.7 mmol) was added. The solutionwas stirred at -78° C. for 165 minutes and then methanol (24 drops) andwater (220 mL) were added. The aqueous layer was extracted with ethylacetate (5×30 mL). The organic layers were combined, dried overanhydrous sodium sulfate, filtered and concentrated by rotaryevaporation to give a crude solid (722 mg). The aqueous layer wasallowed to stand for 17 hours and then re-extracted with ethyl acetate(2×200 mL). The organic layers were treated as described above. Allcrude material was combined to give a solid (772 mg. 81% crude yield).

To a solution of pyridine (1.80 mL, 22.8 mmol) in dichloromethane (17mL) was added chromium (VI) oxide (1.15 g, 11.5 mmol) in two portionsover 10 minutes. The resulting mixture was stirred for 30 minutes. Tothis solution was added the previously isolated solid (760 mg) and thesolution was stirred for 24 hours. The dichloromethane solution wasseparated by decanting and the residue was washed with dichloromethane(5×50 mL). The combined organic layers were washed with 1N aqueoushydrochloric acid (187 mL). The aqueous extract was diluted with water(200 mL) and extracted with dichloromethane (5×200 mL) and ethyl acetate(3×200 mL). All organic layers were combined and filtered, partiallyconcentrated by rotary evaporation, dried over anhydrous sodium sulfate,and concentrated by rotary evaporation to yield a light tan powder. Thiscrude product was purified by flash chromatography eluting withchloroform:ethyl acetate (80:20) to give the title compound as a whitesolid (509 mg, 62%; Rf 0.67, hexanes:ethyl acetate 1:1).

EXAMPLE 20 (c)7-Chloro-3-formylpyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

A solution of1-(4-methoxyphenylmethyl)-7-chloro-3-formylpyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dioneor2-(4-methoxyphenylmethyl)-7-chloro-3-formylpyrazolo[3,4-c][1]benzazepine-4,10(2H,9H)-dionefrom Example 20(b) above (400 mg, 1.01 mmol) and ceric ammonium nitrate(2.2 g, 4.03 mmol) in a mixture of acetonitrile (12 mL) and water (4 mL)was stirred for 17 hours at room temperature and filtered. The isolatedsolid was washed with a mixture of acetonitrile (12 mL) and water (4 mL)followed by acetone (10 mL). The acetonitrile-water solutions wereextracted with ethyl acetate. The solid material from above was combinedwith the ethyl acetate extract and solvent was removed by rotaryevaporation. The residue was washed with hot methanol (1×20 mL then 1×10mL) and dried to give the title compound (25 mg, 9%).

EXAMPLE 2 1 (a) Ethyl 4-(4-chloro-2-nitrobenzoyl)-3-benzoyl-1H-pyrazole-5-carboxylate

A solution of ethyl 4-(4-chloro-2-nitrophenyl)-4-oxo-2-butynoate(prepared as described in Example 48(a)) (1.2 g, 4.11 mmol) anddiazoacetophenone (1.2 g 8.22 mmol, prepared as described in Org. Syn.Coll. Vol. VI. pp. 386-388) in tetrahydrofiuran (THF) (21.6 mL) wasstirred at room temperature for 16 hours. The reaction was concentratedby rotary evaporation and purified by flash chromatography eluting withhexanes:ethyl acetate (90:10, 80:20, 70:30) to give the title compound(1.3 g, 74.3%); R_(f) 0.38 (1:1 ethyl acetate:hexanes).

(b) Ethyl4-(4-chloro-2-aminobenzoyl)-3-benzoyl-1H-pyrazole-5-carboxylate

Following a procedure similar to that described in Example 23(d), ethyl4-(4-chloro-2-nitrobenzoyl)-3-benzoyl-1H-pyrazole-5-carboxylate (1.2g2.81 mmol) was treated with nickel boride to afford crude product. Thecrude product was purified by flash chromatography eluting withhexanes:ethyl acetate (75:25-50:50) to give the title compound as asolid (620 mg, 56%).

(c) 3-Benzoyl-7-chloropyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

A solution of ethyl4-(4-chloro-2-aminobenzoyl)-3-benzoyl-1H-pyrazole-5-carboxylate (620 mg,1.56 mmol), 1-methyl-2-pyrrolidinone (4 mL) and ammonium acetate (120mg, 1.56 mmol) was heated at 146° C. for 16.5 hours. The temperature wasincreased to 160° C. for 1 hour. The solution was allowed to cool toroom temperature and water (60 mL) was added. The insoluble material(468 mg) was filtered, dried, and twice subjected to flashchromatography eluting with hexanes:ethyl acetate (90:10-50:50) to giveimpure product. The crude solid was triturated with ethanol (15 mL),washed with ethanol (3×10 mL) and dried to give the title compound (30.5mg, 5.6% yield m.p. 370-373° C. dec.).

EXAMPLE 22 (a) N-benzyloxybenzylideneamine

To a mixture of ethanol (100 mL), potassium carbonate (8.98 g, 65 mmol),and O-benzylhydroxylamine hydrochloride (10.0 g, 62.7 mmol) was addedbenzaldehvde (6.65 g, 62.7 mmol). The mixture was refluxed for 5 hours,allowed to cool to room temperature, and diluted with water (500 mL).The aqueous solution was extracted with ethyl acetate (500 mL). Theorganic layer was washed with water, dried over magnesium sulfate,filtered, and concentrated by rotary evaporation to give the titlecompound as a yellow oil (14.96 g, 119%).

(b) N,O-Dibenzylhydroxylamine hydrochloride

To a solution of crude N-benzyloxybenzylideneamine from Example 22(a)(3.0 g, 14.2 mmol) in dichloromethane (30 mL) at 0° C. was addeddimethylphenylsilane (3.09 mL, 20.3 mmol) followed by trifluoroaceticacid (3.92 mL, 50.6 mmol). The solution was allowed to warm to roomtemperature and was stirred for 16 hours. The solution was concentratedby rotary evaporation. To the crude oil was added dichloromethane (20mL) and a hydrogen chloride saturated solution of dichloromethane (20mL). The insoluble material (300 mg) was filtered and the solution wasconcentrated by rotary evaporation. To the crude oil was added ahydrogen chloride saturated solution of ether (20 mL). Additional ether(100 mL) was added and the insoluble material was filtered. The solidobtained was combined with the initial solid filtered above to give thetitle compound (1.57 g, 45%).

(c)7-Chloro-3-[(N-hydroxy-N-benzylamino)carbonyl]pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

A solution of7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (459mg, 1.7 mmol) (compound of Example 9) and 1,1'-carbonyldiimidazole (421mg, 2.6 mmol) in N,N-dimethylformamide (3 mL) was heated at 50° C. for 1hour. In one portion N,O-dibenzylhydroxylamine hydrochloride (1.3 mg,5.24 mmol) was added and the solution was heated at 50° C. for 1 hour.The reaction was cooled to room temperature and water (35 mL) was added.The aqueous layer was extracted with ethyl acetate (3×100 mL). Theorganic layers were concentrated by rotary evaporation to a volume of 15mL and the insoluble material was filtered. The organic layer wasconcentrated by rotary evaporation and to the residue was added methanol(10 mL). The insoluble material was filtered and all solids werecombined and dried to give a white solid (500 mg). To this solid wasslowly added 10% aqueous sodium hydroxide (10-13 mL) until pH 11 wasachieved. The insoluble material was removed by filtration and to thebasic solution was added concentrated glacial acetic acid (3-4 mL) untila solid precipitated out. The insoluble material was filtered and driedto give the title compound (259 mg, 40.3%, m.p. 282-285° C.).

EXAMPLE 23 (a) 2,2,2-Trifluorodiazoethane

To a solution of 3,3,3-trifluoroethylamine hydrochloride (14.8 g, 109mmol) in water (55 mL) was added diethyl ether (82 mL) followed bysodium nitrite (8.2 g, 119 mmol). The reaction was sealed with a TEFLON™stopper and stirred at room temperature for 3 hours. The layers wereseparated and the volume of the ether layer was measured to be 82 mL.The trifluorodiazoethane concentration of the ether solution wasdetermined to be 0.7M as described below, for a yield of 52.5% (6.31 g)of 2,2,2-trifluorodiazoethane.

A 1.00 mL aliquot of ethereal trifluorodiazoethane was added to avigorously stirred solution of excess p-toluenesulfonic acid monohydrate(510 mg, 2.68 mmol) in diethyl ether (10 mL). Water (10 mL) was added,followed by a few drops of phenolphthalein indicator. The mixture wastitrated to a pink end point with 0.2N aqueous sodium hydroxide solution(9.9 mL), demonstrating that 0.7 mmol of p-toluenesulfonic acid had beenconsumed by reaction with 2,2,2-trifluorodiazoethane.

(b) Ethyl3-trifluoromethyl-4-[(4-chloro-2-nitrophenyl)(hydroxy)methyl]1H-pyrazole-5-carboxylate

The ethereal 2,2,2-trifluorodiazoethane solution (80 mL, 56 mmol) fromExample 23(a) above was added to ethyl4-(4-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate (3.09 g, 10.9 mmol) andthe solution was stirred at room temperature for 3 days. TLC showedtraces of remaining starting material (R_(f) 0.67, 1:1 ethylacetate:hexanes) and two new products (R_(f) 0.36, 0.48). Excess2,2,2-trifluorodiazoethane was quenched by slow addition of a solutionof p-toluenesulfonic acid in diethyl ether.

This sequence (Examples 23(a) and (b)) was repeated exactly as describedabove (in the second run the 2,2,2-trifluorodiazoethane concentrationwas determined to be 0.54M, for a yield of 4.78 g, 40%) and theresulting diethyl ether solutions were combined, washed with water (1×50mL then 2×75 mL) and saturated aqueous sodium chloride (1×75 mL), driedover anhydrous sodium sulfate, filtered, and concentrated to give anorange-red oil (20 g). This material was purified by flashchromatography (hexane:ethyl acetate; 90:10 then 80:20) to give puretitle compound (2.39 g, 28%) and a mixture of regioisomers (0.88 g).

(c) Ethyl4-(4-chloro-2-nitrobenzoyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylate

Chromium(VI) oxide (CrO₃, 2.828 g, 28.28 mmol) was added to a solutionof pyridine (4.58 mL, 56.63 mmol) in dichioromethane (70 mL) and themixture was stirred at room temperature for 15 minutes. To the resultingburgundy-colored solution was added a solution of ethyl3-trifluoromethyl-4-[(4-chloro-2-nitro-phenyl)(hydroxy)methyl]-1H-pyrazole-5-carboxylate(1.64 g, 4.17 mmol) in dichloromethane (15 mL). The resulting mixturewas stirred at room temperature for 4 days. The dichloromethane solutionwas decanted from the dark viscous residue, which was washed withdiethyl ether (3×100 mL). The dichloromethane and diethyl ether extractswere combined, washed successively with 1N aqueous hydrochloric acid(2×100 mL) and saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate, filtered, and concentrated by rotary evaporation toafford 1.33 g (82%) of the title compound as a yellow solid.

(d) Ethyl4(4-chloro-2-aminobenzoyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylate

Nickel boride (Ni₂ B, PYROPHORIC) was generated by slow addition (over15 minutes, so that the internal temperature remained between 10° C. and16° C.) of a (cloudy) solution of sodium borohydride (NaBH₄, 1.22 g,32.25 mmol) in water (16 mL) to a cooled (to 10° C. using an ice waterbath) solution of nickel(II) acetate tetrahydrate [Ni(OAc)₂ ·4H₂ O](2.02 g, 8.12 mmol) in water (30 mL). A granular black precipitateformed immediately as the sodium borohydride solution was added. Aftercompletion of the addition the mixture was stirred at 10-15° C. for 2hours. The black precipitate was separated by vacuum filtration througha medium frit under a nitrogen atmosphere provided by blowing nitrogenthrough an inverted funnel suspended above the filtration. The blackprecipitate was washed with water (3×10 mL) and ethanol (3×10 mL),giving 1.06 g of a fine black powder. This material was used immediatelyfor the following reaction; use of material which had been storedovernight gave unsatisfactory results.

The freshly prepared nickel boride (1.06 g) was added to a solution ofethyl 4-(4-chloro-2-nitrobenzoyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylate (437.0 mg, 1.116 mmol) inethanol (20 mL) followed by addition of 1.0N aqueous hydrochloric acid(5.0 mL). This mixture was stirred at 60° C. for 30 minutes and then atroom temperature overnight (17 hours). The reaction mixture was pouredinto water (250 mL) and extracted with diethyl ether (2×250 mL). Theorganic extract was filtered to remove residual black solids, washedsuccessively with water (250 mL) and saturated aqueous sodium chloride(250 mL), dried over anhydrous magnesium sulfate, filtered, andconcentrated by rotary evaporation to afford 0.42 g of greenish-yellowsolid. This material was dissolved in ethyl acetate (50 mL) andpreabsorbed onto 4.1 g of silica gel, which was then applied to the topof a 40 g (2.84×14.2 cm) silica gel flash chromatography column. Thecolumn was eluted with hexane-ethyl acetate (90:10 then 80:20) to give235.6 mg (58.41%) of the title compound as a light yellow solid.

(e)7-Chloro-3-trifluoromethylpyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

To a solution of ethyl4-(4-chloro-2-aminobenzoyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylate(360 mg, 0.997 mmol) in toluene (50 mL) was added 2-hydroxypyridine(93.9 mg, 0.988 mmol). Toluene was removed by distillation and theresidue was heated at 170° C. for 2 days. The flask was cooled to roomtemperature and dichloromethane (20 mL) was added. The insolublematerial was filtered to give crude solid (284 mg). The crude materialwas continuously chromatographed eluting with dichloromethane (100 mL)and dichloromethane:2-propanol (98:2, 200 mL). The fractions wereconcentrated bv rotary evaporation and were found to contain acontaminant from tygon tubing. The fractions were combined and flashchromatographed through a plug of silica gel to remove the contaminant,eluting with hexanes, hexanes:ethyl acetate (95:5, 90:10),dichloromethane, and dichloromethane:2-propanol (95:5, 90:10). Theproduct fractions were concentrated by rotary evaporation to give thetitle compound as a white solid (124 mg, 37%. m.p. 337-339° C.).

Alternatively, the title compound can be preferably prepared as follows:A mixture of ethyl4-(4-chloro-2-aminobenzoyl)-3-trifluoromethyl-1H-pyrazole-5-carboxylate(1.0 g, 2.76 mmol), ammonium acetate (0.21 g, 2.76 mmol) and1-methyl-2-pyrrolidinone (2.3 mL) was heated with stirring at 160° C.under N₂ for one hour. After cooling to room temperature, water (25 mL)was added to the stirred reaction mixture. The resulting aqueous mixturewas filtered after stirring for ten minutes. The filter cake was washedwith water (2×25 mL) then dried under vacuum to give a tan solid. Thesolid was placed in methylene chloride (25 mL) and the mixture wasstirred for fifteen minutes, then filtered. The filter cake was washedwith methylene chloride (2×25 mL) and dried under vacuum to give thetitle compound as a tan solid (0.66 g, 76%, m.p. 334-336° C.).

EXAMPLE 247-Chloro-3-[(N-phenyl-N-methylamino)carbonyl]pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

To a suspension of7-chloro-3-(carboxy)pyrazolo[3,4c][1]-benzazepine-4,10(1H,9H)-dione (500mg, 1.72 mmol) (compound of Example 9) in carbon tetrachloride (5 mL)was added phosphorus pentachloride (358 mg, 1.72 mmol). The mixture wasstirred for 17 hours, filtered and washed with carbon tetrachloride(3×10 mL). To the residue was added N-methylaniline (190 μL, 1.72 mmol)and dioxane (7 mL). The resulting mixture was stirred 17 hours. To thismixture was added water (50 mL). The aqueous layer was separated andextracted with ethyl acetate (3×100 mL). The organic layers werecombined and concentrated by rotary evaporation to 50 mL. The insolublematerial was removed by filtration and the organic solution waspreabsorbed onto silica gel and purified by flash chromatography elutingwith chloroform and chloroform:2-propanol (99:1, 98:2-90:10). Theproduct fractions were combined and concentrated by rotarv evaporationto give the title compound as a light yellow solid (100 mg, 15.2%, m.p.308° C.).

EXAMPLE 25 (a) Benzaldehyde Tosylhydrazone

To a slurry of p-toluenesulfonylhydrazide (1.05 g, 5.63 mmol) inabsolute methanol (5 mL) was added freshly distilled benzaldehyde (0.5g,4.7 mmol). The p-tosythydrazide dissolved giving a clear solution.Within 7-10 minutes of stirring at room temperature, the title compoundbegan to crystallize. The reaction mixture was cooled to -15° C. for 5minutes. The solid was filtered, washed with 15 mL of cold methanol anddried under aspirator vacuum to yield off-white crystals of the titlecompound (1.31 g, 100%, m.p. 135.5-136.1° C.).

(b) Phenyldiazomethane

In an oven-dried round bottom flask was placed benzaldehydetosylhydrazone (1.15 g, 4.2 mmol), followed by 4.3 mL of a 1.0M solutionof sodium methoxide in methanol (2.3 g Na metal dissolved in absolutemethanol and diluted to 100 mL). The mixture was swirled until all thecontents dissolved. Most of the solvent was removed via romy evaporationand the last traces of solvent by evacuation of the flask under highvacuum for 2 hours. The solid obtained was subjected to a Kugelrohrdistillation at 215° C. and 200 millitorr for 1 hour. At 68-70° C., thetitle compound, as a red oil, was collected in a receiver flask in aquantitative yield.

(c) Ethyl3-phenyl-4-[(4-chloro-2-nitrophenyl)(hydroxy)methyl-1-H-pyrazole-5-carboxylate

A solution of freshly generated phenyldiazomethane (2.44 g, 20.7 mmol)in 10 mL of anhydrous THF was added to ethyl4-(4-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate (5.86 g, 20.7 mmol) in10 mL THF and the mixture was stirred at room temperature for 18 hours.The reaction mixture was quenched with excess ethereal acetic acid andconcentrated via rotary evaporation to an oil (12.24 g) which solidifiedon cooling. This was filtered to yield the title compound as a paleyellow solid (2.42 g). The filtrate was concentrated via rotaryevaporation to an oil which was triturated with hexane:ethyl acetate(4:1) to yield an additional 1.52 g of the title compound (48% combinedyield).

(d) Ethyl 3-phenyl-4-(4-chloro-2-nitrobenzoyl)-1H-pyrazole-5-carboxylate

To a solution of dry pyridine (0.237 g, 300 mmol) in anhydrous methylenechloride (5 mL) was slowly added chromium trioxide (0.15 g, 1.5 mmol) togive a wine colored mixture which was stirred at room temperature for 10minutes. A solution of ethyl3-phenyl4[(4-chloro-2-nitrophenyl)-(hydroxy)methyl]-1H-pyrazole-5-carboxylate(0.10 g, 0.25 mmol) in anhydrous methylene chloride (2 mL) was added tothe wine red mixture in three portions over 25 minutes. The reactionmixture was stirred at room temperature for 18 hours. The reactionmixture was filtered and the filtrate extracted with 3×20 mL 3N HCl. Thecombined organic extracts were dried with sodium sulfate andconcentrated via rotary evaporation to give an oil (0.1 g) which wastriturated with hexane:ethyl acetate (4:1) to give the title compound asa tan solid (0.075 g, 75%).

(e) Nickel Boride

A mixture of nickel(II) acetate tetrahydrate (2.0 g, 8.0 mmol) in water(30 mL) was stirred at room temperature to produce a green solutionwhich was cooled to 0° C. Sodium borohydride (1.21 g, 32 mmol) in water(16 mL) was added dropwise over 30 minutes via pipet to the greensolution maintaining the temperature at 11-12° C. The resulting blackslurry was filtered, washed with water (3×25 mL) and ethanol (3×10 mL)and dried under aspirator vacuum and a blanket of N₂, taking care to notdry the solid too much as it may ignite. Yield of wet, black solidrecovered (0.82 g, 1.37×theoretical yield).

(f) Ethyl 3-phenyl-4-(4-chloro-2-aminobenzoyl)-1H-pyrazole-5-carboxylate

A suspension of nickel boride (3.56 g) and 1N HCl (16 mL) in methanol(65 mL) was added to ethyl3-phenyl-4-(4-chloro-2-nitrobenzoyl)-1H-pyrazole-5-carboxylate (1.5 g,3.7 mmol) and the mixture heated to 60° C. for 18 hours. The reactionmixture was filtered and the filtrate concentrated via rotovap to agreen solid (2.38 g). The solid was dissolved in ethyl acetate (100 mL)and extracted with water (2×50 mL) and brine (1×50 mL). The organiclayer was dried over sodium sulfate and concentrated to a dark green oil(1.5 g) which was washed with a small amount of hexanes to yield thetitle compound as a yellow solid (0.855 g, 62%).

(g) 7-Chloro-3-phenylpyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione

A mixture of ethyl3-phenyl-4-(4-chloro-2-aminobenzoyl)-1H-pyrazole-5-carboxylate (0.84 g,2.28 mmol) and 2-hydroxy-pyridine (0.217 g, 2.28 mmol) in toluene (12mL) was distilled at 160° C. until all the toluene was removed. Theresidue was heated at the same temperature for 18 hours. The reactionresidue was washed with water to remove the 2-hydroxy-pyridine. Theinsoluble material was added to methanol (225 mL) and heated to boiling.Ethyl acetate (100 mL) was added and the solution heated for anadditional 2 minutes, then concentrated to 100 mL. The solution wasfiltered to remove some insoluble material and the filtrate concentratedvia rotovap until a precipitate formed which was filtered to give thetitle compound as a tan solid (0.381 g, 51%, mp 328.1-330.9° C.).

Various other compounds of the Formula I, wherein X is O and C is apyrazole ring, were prepared utilizing the procedures described ingeneral procedures A, B and C and are illustrated in Table 1.

GENERAL PROCEDURES

PROCEDURE A

To an oven-dried flask was added7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione(0.50 g, 1.58 mmol) and an appropriate alcohol of the Formula IV (R⁵ OH)(10 mL). To the resulting slurry was added titanium (IV) isopropoxide(0.89 g, 3.14 mmol) via syringe and the mixture was heated to reflux for10-90 minutes. The reaction mixture was quenched with 1N HCl (20 mL).Ether (30 mL) was added and any insoluble material was removed byfiltration. The filtrate was extracted with ether (3×30 mL). Thecombined organic extracts were dried over Na₂ SO₄ and concentrated viarotary evaporator to give the crude product. The solid wasrecrystallized from methanol to afford the compounds of the formula Iwhich are listed in Table 1.

PROCEDURE B

(a) Preparation of catalyst for Procedure B Di-n-butyltindiisothiocyanate

Di-n-butyltin oxide (3.36 g, 13.5 mmol) and ammonium thiocyanate (2.05g, 27.0 mmol) were suspended in methylcyclohexane (125 mL) in a flaskequipped with a nitrogen gas inlet and a Dean-Stark trap. The reactionmixture was slowly heated to reflux with vigorous stirring and refluxedfor 18 hours. Methylcyclohexane (100 mL) was removed via rotaryevaporator and an insoluble mass settled. Chloroform (80 mL) was addedand the mixture heated to boiling, then filtered to remove unreactedammoni un thiocyanate. The filtrate which had begun to crystallize wasconcentrated to 50 mL under a stream of nitrogen and filtered to give anoff-white solid. Recrystallization from methylene chloride gave thetitle compound as a white solid (2.13 g, 45%, mp 151° C.).

1-Hydroxy-3-(isothiocyanato)-tetrabutyldistannoxane

A mixture of di-n-butyltin oxide (2.14 g, 8.6 mmol) and di-n-butyltindiisothiocyanate (1.0 g, 2.8 mmol) in ethanol (30 mL) was heated toreflux for 6 hours during which time the white slurry became a clearsolution. The reaction mixture was concentrated via rotary evaporator toa solid which was pulverized and left exposed at ambient temperature for18 hours. The powder was recrystallized from hexanes at 0° C. to givethe title compound as a white solid (2.74 g, 86%).

(b) The Procedure

A toluene solution (10 mL) of7-chloro-3-(ethoxy-carbonyl)pyrazolo[3,4-c][1](benzazepine-4,10(1H,9H)-dione(0.50 g, 1.58 mmol), an appropriate alcohol of the Formula IV (R⁵ OH)(15.8 mmol) and 1-hydroxy-3-(isothiocyanato)tetrabutyl-distannoxane(0.176 g, 0.316 mmol) was heated at reflux for 18 hours. The reactionmixture was concentrated via rotary evaporator to give an impure solid.This solid was subjected to flash chromatography using hexane:ethylacetate (95:5) as the eluent to remove the tin catalyst and methylenechloride:methanol (50:50) to recover the product, which was furtherpurified by recrystallization from methanol to afford the compounds ofthe Formula I which are listed in Table 1.

PROCEDURE C

To a flame-dried flask was added 7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (0.50 g, 1.7 mmol)(compound of Example 9) and anhydrous methylene chloride (10 mL). To theresulting slurrv was added oxalyl is chloride (0.43 g, 3.4 mmol) andanhydrous dimethylformamide (2 drops) and the reaction mixture wasstirred at room temperature for 1 hour. An aliquot of the reactionmixture was quenched with methanol to check for complete formation ofthe methyl ester which indicated that formation of the acid chloride wascomplete. The reaction mixture was concentrated via rotary evaporatorand immediately treated with an appropriate alcohol of the formula IV(R⁵ OH) (5-10 mL) at 100° C. for 15 minutes. The slurry was filtered andwashed with water to recover the crude product. Any precipitated solidin the filtrate was recovered and combined with the previous solid. Thecombined solids were recrystallized from methanol to afford thecompounds of the formula I which are listed in Table 1.

                                      TABLE I                                     __________________________________________________________________________     ##STR26##                                                                                                Alcohol of the                                    Example                     Formula IV                                        No.  R.sup.1                                                                         R.sup.2                                                                         R.sup.3                                                                         R.sup.4                                                                         R              (R.sup.5 OH)                                                                              Procedure                                                                          Yield                                                                            m.p. ° C.              __________________________________________________________________________    18   H H Cl                                                                              H --C(O)OCH(CH.sub.3).sub.2                                                                    HOCH(CH.sub.3).sub.2                                                                      A    80 301                           26.sup.(a)                                                                         H H Cl                                                                              H --C(O)OCH(CH.sub.3)Et                                                                        HOCH(CH.sub.3)Et                                                                          A    40 287.8-289.5                   27.sup.(a)                                                                         H H Cl                                                                              H --C(O)O(CH.sub.2).sub.3 CH.sub.3                                                             HO(CH.sub.2).sub.3 CH.sub.3                                                               A    60 259.5-261.1                   28.sup.(a)                                                                         H H Cl                                                                              H --C(O)O(CH.sub.2).sub.2 CH.sub.3                                                             HO(CH.sub.2).sub.2 CH.sub.3                                                               A    61 272.6-273.3                   29.sup.(a)                                                                         H H Cl                                                                              H --C(O)O(CH.sub.2).sub.2 Ph                                                                   HO(CH.sub.2).sub.2 Ph                                                                     A    56 227.6                         30.sup.(a)                                                                         H H Cl                                                                              H --C(O)OCH.sub.2 CH(CH.sub.3).sub.2                                                           HOCH.sub.2 CH(CH.sub.3).sub.2                                                             A    76 282.7-283.6                   31.sup.(a)                                                                         H H Cl                                                                              H --C(O)O(CH.sub.2).sub.3 Ph                                                                   HO(CH.sub.2).sub.3 Ph                                                                     A    87 225.6-227.5                   32.sup.(a)                                                                         H H Cl                                                                              H --C(O)O(CH.sub.2).sub.2 CH═CH.sub.2                                                      HO(CH.sub.2).sub.2 CH═CH.sub.2                                                        A    62 250.9-251.3                   33.sup.(b)                                                                         H H Cl                                                                              H --C(O)OCH.sub.2 cyclopropyl                                                                  HOCH.sub.2 cyclopropyl                                                                    B    57 269.4-269.6                   34.sup.(a)                                                                         H H Cl                                                                              H --C(O)O(CH.sub.2).sub.3 CH═CH.sub.2                                                      HO(CH.sub.2).sub.3 CH═CH.sub.2                                                        A    75 231.3-233.4                   35.sup.(a)                                                                         H H Cl                                                                              H --C(O)OCH(CH.sub.3)CH.sub.2 CH═CH.sub.2                                                  HOCH(CH.sub.3)CH.sub.2 CH═CH.sub.2                                                    A    55 242.9-244.1                   36   H H Cl                                                                              H --C(O)O(CH.sub.2).sub.2 SCH.sub.3                                                            HO(CH.sub.2).sub.2 SCH.sub.3                                                              C    63 230.9-233.1                   37   H H Cl                                                                              H --C(O)O(CH.sub.2).sub.2 C(CH.sub.3)═CH.sub.2                                             HO(CH.sub.2).sub.2 C(CH.sub.3)═CH.sub.2                                               C    22 234.9-236.2                   38   H H Cl                                                                              H --C(O)OCH.sub.3                                                                              HOCH.sub.3  C    73 302.6 dec.                    39   H H Cl                                                                              H --C(O)O(CH.sub.2).sub.2 C.tbd.CH                                                             HO(CH.sub.2).sub.2 C.tbd.CH                                                               C    21 255-255.6                     40   H H Cl                                                                              H --C(O)O(CH.sub.2).sub.3 SCH.sub.3                                                            HO(CH.sub.2).sub.3 SCH.sub.3                                                              C    60 212.9                         41   H H Cl                                                                              H --C(O)O(CH.sub.2).sub.3 Cl                                                                   HO(CH.sub.2).sub.3 Cl                                                                     C    26 228.9-229.6                   42   H H Cl                                                                              H --C(O)O(CH.sub.2).sub.2 Cl                                                                   HO(CH.sub.2).sub.2 Cl                                                                     C    30 254.9-255.1                   43.sup.(c)                                                                         H H Cl                                                                              H --C(O)OCH.sub.2 CF.sub.3                                                                     HOCH.sub.2 CF.sub.3                                                                       C    23 249.1-256.4                   44   H H Cl                                                                              H --C(O)OCH.sub.2 C.tbd.C--Ph                                                                  HOCH.sub.2 C.tbd.C--Ph                                                                    C    24 231.0-233.1                   __________________________________________________________________________     .sup.(a) contains a small amount (generally less than 10%) of the             corresponding isopropyl ester as an impurity.                                 .sup.(b) contains a small amount (less than 10%) of the corresponding         ethyl ester starting material as an impurity.                                 .sup.(c) 0.2 equivalents of dimethylaminopyridine (DMAP) was also added t     the reaction mixture.                                                    

EXAMPLE 45 7-Chloro-3-((t-butoxy)carbonylmethyl)pyrazolo-[3,4-c][1-benzazepine-4,10(1H,9H)-dion

To a slurry oft-butyl(E)-3-(8-chloro-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepin-4-yl)acrylate(prepared as described in Example 44 of WO94/29275 published Dec. 22,1994) (0.81 g, 2.2 mmol) in methanol (5 mL) was added anhydroushydrazine (0.14 g, 4.5 mmol) dropwise via syringe. The resulting brightyellow mixture immediately darkened to an orange color. After 45 minutesof stirring at room temperature, the reaction mixture became a thickyellow-orange slurry which was allowed to stir for an additional 18hours. The reaction mixture was filtered to give a solid which wasrecrystallized from ethanol. Very little product was recovered and thefiltrate was concentrated and purified with a silica gel plug usingethyl acetate:hexanes (50:50) as the eluent to give an orange oil. Thiswas allowed to crystallize in ethanol at -10° C. for 18 hours, filteredand dried at 100° C. to give the title compound (0.2 g, 25%, m.p.226.5-228.6° C.).

EXAMPLE 467-Chloro-3-(carboxymethyl)pyrazolo[3,4-][1]benzazepine-4,10(1H,9H)-dione

To a mixture of 7-chloro-3-((t-butoxy)carbonylmethyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione (0.26 g, 0.72 mmol) inmethylene chloride (6 mL) was added trifluoroacetic acid (6.38 g, 56mmol) via syringe. The reaction was stirred at room temperature for 30minutes. The reaction mixture was concentrated via rotary evaporator togive a solid which was recrystallized from dimethylformamide and driedat 100° C. to yield the title compound (0.14 g, 64%, mp 297.3-299.6°C.).

EXAMPLE 47 7-Chloro-3-(ethoxycarbonyl)-10-thioxopyrazolo[3,4-c][1]benzazepine-4(1H,9H)-one

To a suspension of Lawesson's Reagent[(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)(0.32g, 0.80 mmol) in dry toluene (15 mL) at room temperature was added7-chloro-3-(ethoxycarbonyl)pyrazolo-[3,4-c][1]benzazepine-4,10(1H,9H)-dione (0.51 g, 1.59 mmol) in one portion. The resulting slurry washeated to reflux for 1.5 hours. The reaction mixture was filtered toremove insoluble material. The filtrate was concentrated via rotaryevaporator to give a green oil which was purified by flashchromatography using chloroform:methanol (9:1) as the eluent. Theyellow-green solid recovered was recrystallized from methanol to givethe title compound (0.44 g, 82%, mp 248.0-252.6° C.).

EXAMPLE 48 (a) Ethyl 4-(4-chloro-2-nitrophenyl)-4-oxo-2-butynoate

To a solution of ethyl 4-(4-chloro-2-nitrophenyl)-4- hydroxy-2-butynoate(7.46 g, 26.3 mmoles) in dichloromethane (350 mL) cooled in an ice-bathwas added manganese dioxide (26.2 g, 301.3 mmol). The reaction mixturewas stirred for 20 minutes and then was allowed to warm to roomtemperature. The reaction mixture was stirred at room temperature for130 minutes and then was filtered twice through a pad of CELITE™. Thefiltrate was purified by flash chromatography on silica gel (195 g),eluting with dichloromethane, to afford 3.80 g (51%) of the titlecompound as a brownish-orange oil.

(b) Ethyl 4-(4-chloro-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate

A solution of ethyl 4-(4-chloro-2-nitrophenyl)-4-oxo-2-butynoate (3.75g, 13.31 mmol) in dimethylformamide (20 mL) was added dropwise to anice-cooled solution of NaN₃ (901 mg, 13.86 mmol) in dimethylformamide(20 mL). The reaction mixture was stirred at ice-bath temperature for3.25 hours and then the solvent was removed in vacuum (0.3 torr)overnight. The brown solid residue was suspended in water (400 mL) andacidified with concentrated hydrochloride acid (2 mL) to pH 1. Themixture was extracted with ether (2×400 mL) and the extracts werecombined, washed with 1N HCl (100 mL), dried over MgSO₄, filtered andconcentrated in vacuo (0.4 torr) to afford 3.96 (92%) of crude titlecompound as a brownish-orange solid. The crude product wasrecrystallized from refluxing toluene (100 mL) to afford 1.98 g (46%) ofthe title compound as pale greenish tan plates.

(c) Ethyl 4-(4-chloro-2-aminobenzoyl)-1H-1,2,3-triazole-5-carboxylate

A suspension of PtO₂ (541.6 mg) in ethanol (50 mL) was shaken underhydrogen (40 psi) in a PARR™ hydrogenator for 19 hours. A solution ofethyl 4-(4-chloro-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate (1.014g, 3.124 mmol) in chloroform (10 mL)/ethanol (200 mL) was then added tothe reaction mixture and shaking on the PARR™ hydrogenator at 51 psi wascontinued. After 3 hours the reaction mixture was filtered through a padof CELITE™, washing with ethanol. The filtrate was concentrated undervacuum (0.3 torr) to afford 0.998 g (108%) of crude title compound as abright yellow foam.

(d) 7-Chloro-1,2,3-triazolo[4,5-c][1]benzazepine-4,10(1H,9H)-dione

A mixture of tetrahydrofuran (15 mL), ethyl4-(4chloro-2-aminobenzoyl)-1H-1,2,3-triazole-5-carboxylate (844.1 mg,2.86 mmol) and potassium t-butoxide (917 mg, 8.17 mmol) was stirred at50-55° C. under argon for 75 minutes. Additional tetrahydrofuran (15 mL)was then added and stirring was continued for another 3.5 hours. Thereaction mixture was quenched with acetic acid (500 μL, 8.73 mmol),followed by water (25 mL) and then was stirred at room temperatureovernight. The product was collected by filtration, washed with water(10 mL) and then ether (5 mL) to afford, after drying in vacuo (0.2torr) at 60° C., 228.9 mg (32%) of crude title compound as a light tanpowder. The aqueous filtrate was refiltered to afford an additional174.1 mg (24%) of the title compound. The title compound (194.5 mg) waspurified by dissolving the compound in a mixture of saturated aqueousNAHCO₃ (1.0 mL), saturated aqueous Na₂ CO₃ (1.0 mL) and water (100 mL)with heating (60° C.) and sonication and then acidifying the hot mixturewith 3N HCl to a pH of about 2. A white precipitate formed which wascollected by filtration and dried in vacuo (0.3 torr) at 60° C. toafford 154.1 mg (21.6%) of the title compound, m.p. 385-388° C.

EXAMPLE 49 (a) Ethyl 4-(5-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate

To a solution of ethyl propiolate (4.05 mL, 40 mmol) in tetrahydrofuran(125 mL) at -78° C. under nitrogen was added n-BuLi (2.5 mL, 40 mmol,1.6M in hexane). The reaction mixture was stirred at about -70° C. for0.5 hours and then 2-nitro-5-chlorobenzaldehyde (6.75 g, 36.4 mmol) wasadded dropwise. The reaction mixture was stirred at -78° C. for 0.25hours, warmed to -60° C., quenched with acetic acid (5 mL) and thenwarmed to room temperature. The reaction mixture was partitioned betweenether (250 mL) and water (250 mL). The layers were separated and theorganic layer was washed with brine (250 mL) and dried over Na₂ SO₄. Themixture was filtered and the filtrate was concentrated in vacuo. Theresidue was purified by flash chromatography eluting with hexane/ethylacetate (4:1) to afford 6.12 g (59%) of the title compound as a yellowoil which solidified on standing.

(b) Ethyl 4-(5-chloro-2-nitrophenyl)-4-oxo-2-butynoate

Following a procedure substantially similar to that described in Example48(a), the is title compound (2.28 g, 38%) was obtained from ethyl4-(5-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate (6.12 g, 21.6 mmol),MnO₂ (24.0 g, 276 mmol) and CH₂ Cl₂ (350 mL). The title compound waspurified by flash chromatography eluting with hexane:ethyl acetate(4:1).

(c) Ethyl 4-(5-chloro-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate

Following a procedure substantially similar to that described in Example48(b), the title compound (1.474 g, 69%, as an off-white powder) wasobtained from ethyl 4-(5-chloro-2-nitrophenyl)-4-oxo-2-butynoate (1.85g, 6.6 mmol), NaN₃ (0.45 g, 6.9 mmol) and dimethylformamide (60 mL). Thetitle compound was purified by recrystallization from hothexane:ethylacetate (2:1, 50 mL).

(d) Ethyl 4-(5-chloro-2-aminobenzoyl)-1H-1,2,3-triazole-5-carboxylate

Following a procedure substantially similar to the procedure describedin Example 48(c), the title compound (0.211 g crude) was obtained fromethyl 4-(5-chloro-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate (0.19g, 0.6 mmol), PtO₂ (0.10 g), ethanol (65 mL) and chloroform (5 mL).

(e) 6-Chloro-1,2,3-triazolo[4,5-c][1]benzazepine-4,10(1H,9H)dione

Following a procedure substantially similar to that described in Example48(d), the title compound (0.304 g, 59%, m.p. >250° C., as an off-whitepowder) was obtained (after drying in vacuo at 80° C.) from ethyl4-(5-chloro-2-amino-benzoyl)-1H-1,2,3-triazole-5-carboxylate (0.61 g,2.1 mmol) potassium t-butoxide (0.673 g, 6.0 mmol) and tetrahydrofuran(30 mL).

EXAMPLE 50 (a) Ethyl 4-(6-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate

Following a procedure substantially similar to that described in Example49(a), the title compound (6.44 g, 76%, brown-red oil) was obtained,after purification by flash chromatography eluting with hexane/ethylacetate (5:1 to 3:1), from ethyl propiolate (3.3 mL 33 mmol),tetrahydrofuran (130 mL), n-BuLi (21 mL, 33 mmol, 1.6M in hexane) and2-nitro-6-chlorobenzaldehyde (5.6 g, 30 mmol).

(b) Ethyl 4-(6-chloro-2-nitrophenyl)-4-oxo-2-butynoate

Following a procedure substantially similar to that described in Example49(b), the title compound (4.36 g, 68%, yellow oil) was obtained, afterpurification by flash chromatography eluting with hexane:ethyl acetate(3:1), from ethyl 4-6-chloro-2-nitrophenyl)-4-hydroxy-2-butynoate (6.44g, 22.0 mmol), MnO₂ (23.7 g, 273 mmol) and dichloromethane (360 mL).

(c) Ethyl 4-(6-chloro-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate

Following a procedure similar to that described in Example 49(c), thetitle compound (3.79 g, 87%, orange solid) was obtained from ethyl4-(6-chloro-2-nitrophenyl)-4oxo-2-butynoate (3.8 g, 13.5 mmol), NaN₃(0.92 g, 14.2 mmol) and dimethylformamide (100 mL).

(d) Ethyl 4-(6-chloro-2-aminobenzoyl)-1H-1,2,3-triazole-5-carboxylate

Following a procedure substantially similar to that described in Example49(d), the title compound (0.7823 g, 86%, yellow powder) was obtained,after purification by flash chromatography eluting withtoluene/methanol/CH₃ CO₂ H (80:20:1), followed by trituration withhexane:ether (1:1, 30 mL), from ethyl4-(6-chloro-2-nitrobenzoyl)-1H-1,2,3-triazole-5-carboxylate (1.0 g, 3.1mmol), PtO₂ (0.5 g), and ethanol(290 mL).

(e) 5-Chloro-1,2,3-triazolo[4,5-c][1]benzazepine-4,10(1H,9H)-dione

To a solution of potassium t-butoxide (0.91 g, 8.1 mmol) intetrahydrofuran (25 mL) at room temperature under nitrogen was addedethyl 4(6-chloro-2-aminobenzoyl)-1H-1,2,3-triazole-5-carboxylate (0.7823g, 2.7 mmol) in tetrahydrofuran (25 mL). The reaction mixture wasstirred for 2 hours and then was quenched with acetic acid (2 mL). ThepH of the reaction mixture was adjusted to about 2 by the addition ofconcentrated hydrochloric acid and a solid formed which was collected byfiltration (the acidic filtrate was saved for later use). The solid wasdissolved in water and the aqueous layer was extracted with ethylacetate. The organic layer was concentrated in vacuo and the residuethus obtained was combined wvith acidic filtrate. This mixture was thentriturated with the aqueous layer and a brown solid formed which wascollected by filtration and washed with water (2×10 mL) and hexane (2×10mL). The solid was recrystallized from hot ethyl acetate to afford 0.059g (9%) of the title compound as a light tan powder, m.p. >250° C.

EXAMPLE 51

Following conventional procedures well known in the pharmaceutical artit is contemplated that the following representative pharmaceuticaldosage forms containing a compound of formula I can be prepared.

    ______________________________________                                        (a) Tablet                                                                                            mg/tablet                                             ______________________________________                                        Compound of Formula I   50.0                                                  Mannitol. USP           223.75                                                Croscarmellose sodium   6.0                                                   Maize starch            15.0                                                  Hydroxypropylmethylcellulose (HPMC), USP                                                              2.25                                                  Magnesium stearate      3.0                                                   ______________________________________                                        (b) Capsule                                                                                           mg/capsule                                            ______________________________________                                        Compound of Formula I   10.0                                                  Mannitol, USP           488.5                                                 Croscarmellose sodium   15.0                                                  Magnesium stearate      1.5                                                   ______________________________________                                    

(c) Injection

A sterile aqueous solution for intravenous administration may beprepared by dissolving a compound of Formula I in distilled watercontaining hydroxypropylmethylcellulose (0.5% by weight) and Tween 80(0.1% by weight).

Representative examples of the compounds of the invention have beenfound to possess valuable pharmacological properties. In particular,they have been found to function as antagonists of the effects whichexcitatory amino acids, such as glutamate, have upon the NMDA receptorcomplex. The compounds of the invention are thus useful in the treatmentof neurological disorders, i.e., strokes and/or other neurodegenerativedisorders such as hypoglycemia cerebral palsy, transient cerebralischemic attack, perinatal asphyxia epilepsy, psychosis, Huntington'schorea, arnotrophic lateral sclerosis, Alzheimer's disease, Parkinson'sdisease, Olivo-pontocerbellar atrophy, viral-induced neurodegenerationsuch as in acquired immunodeficiency syndrome and its associateddementia, anoxia such as from drowning, spinal cord and brain trauma,poisoning by exogenous neurotoxins, and chronic pain, for the preventionof drug and alcohol withdrawal symptoms and for the inhibition oftolerance and dependence to opiate analgesics.

The compounds of the invention are particularly useful in reducingneurological degeneration such as can be induced by stroke and theassociated functional impairment which can result.

Treatment using a compound of the invention can be remedial ortherapeutic as by administering a compound of the instant inventionfollowing an ischemic event to mitigate the effects of that event.Treatment can also be prophylactic or prospective by administering acompound of the instant invention in anticipation that an ischemic eventmay occur, for example in a patient who is prone to stroke.

The pharmacological properties of representative examples of thecompounds of the invention were demonstrated by one or more of thefollowing conventional in vitro and in vivo biological test procedures.

In Vitro Procedures

[³ H]-glycine Binding Assay

In the [³ H]-glycine binding assay, neuronal synaptic membranes areprepared from adult (about 250 g) male Sprague-Dawley rats. Freshlydissected cortices and hippocampi are homogenized in 0.32M sucrose (110mg/mL). Synaptosomes are isolated by centrifugation (1000×g, 10minutes), the supernatant is pelleted (20,000×g, 20 minutes) resuspendedin double-distilled water. The suspension was centrifuged for 20 minutesat 8,000×g. The resulting supernatant and buffy coat are washed twice(48,000×g, 10 minutes, resuspension in double-deionized water). Thefinal pellet is quickly frozen (dry icelethanol bath) underdouble-deionized water and stored at -70° C.

On the day of the experiment, thawed synaptic membranes are homogenizedwith a Brinkmann Polytron (TM, Brinkmann Instruments, Westbury, N.Y.)tissue homogenizer in 50 mM tris(hydroxymethyl)aminomethane citrate, pH7.1. The membranes are incubated with 0.04% Sufact-AMPS X100 (TM,Pierce, Rockford, Ill.) in buffer for 20 minutes at 37° C. and washedsix times by centrifugation (48,000×g, 10 minutes) and resuspended inbuffer. The final pellet is homogenized at 200 mg wet weight/mL of thebuffer for the binding assay.

For [³ H]-glycine binding at the N-methyl-D-aspartate receptor, 20 nM [³H]-glycine (40-60 Ci/mmol, New England Nuclear, Boston, Mass.) isincubated with the membranes suspended in 50 mMtris(hydroxymethyl)aminomethane citrate, pH 7.1 for 30 minutes at 4° C.Glycine, 1mM, is used to define the nonspecific binding. Bound [³H]-glycine is isolated from free using a Brandel (Biomedical Researchand Development Laboratories, Gaithersburg, Md.) cell harvester forvacuum filtration over glass fiber filters (Whatman GFB from Brandel,Gaithersburg, Md.) presoaked in 0.025% polyethylenimine. The samplesretained on the glass fiber filters are rinsed 3 times with a total of2.5 mL ice cold buffer. Radioactivity is estimated by liquidscintillation counting. IC₅₀ values are obtained from a least-squaresregression of a logit-log transformation of the data.

The compounds of Examples 1(e), 2-19, 20(c), 21 (c), 22(c), 23(e), 24,25(g), 26-47, 48(d), 49(e) and 50(e) were tested in the [³ H-glycinebinding assay and were found to possess IC₅₀ values in the range ofabout 0.01 μM to about 100 μM. For example, the compounds of Examples18, 27 and 28 were found to possess IC₅₀ values, respectively of 0.064μM, 0.229 μM and 0.027 μM.

In Vivo Procedures

Gerbil Ischemic Model

Adult female Mongolian gerbils (50-70 g) are anesthetized with 2 to 3%halothane. The bilateral common carotid arteries at the neck are exposedand occluded with microaneurysm clips. After 10 min (unless specified),the clips are removed and the blood flow through the carotid arteries isrestored and the skin is sutured. Test compounds are administeredintraperitoneally both pre- and post-occlusion, for example 45 minutesbefore and 5 minutes after occlusion of the carotid arteries.Sham-operated animals are treated in the same manner except that thearteries are not clamped, gross behavioral observations along with motoractivity are recorded for 2 hours on the first (24 hours) day followingthe occlusion. After 4 days, subjects are sacrificed (decapitation),brains are removed, fixed, sectioned and stained with hematoxylin/eosinand cresyl violet.

The brain sections are rated for neuronal damage in the hippocampususing the following rating scale:

0=undamaged, normal

1=slight damage (up to 25%)--restricted to CA1 subiculum border

2=moderate damage (up to 50%)--obvious damage, restricted to less thanhalf of CA1 field

3=marked damage (up to 75%)--involving greater than half of CA1 field

4=damage extending beyond CA1 field

Sections (7 micron) are evaluated from each brain. Occasionally,asymmetrical damage may be noted and the rating assigned is the averagescore of the two sides. The average brain damage rating score for eachgroup is recorded, and the damage scores of the drug treated group arecompared to the vehicle-treated group using Wilcoxcon-Rank Sum test. Theresults can be reported as the percentage of neuroprotection afforded bya particular dose is and dosing regimen.

Representative test results for the compounds of the instant inventionin the gerbil ischemic model are illustrated by the compound of Example48(d) which was found to provide 77% neuroprotection when administeredintraperitoneally (ip) twice (pre- and post-occlusion) at a dose of 20mg/kg body weight.

Rat Middle Cerebral Artery Test

Male SHR rats weight 280-320 g are used for these studies. The methodused for permanent middle cerebral artery (MCA) occlusion is asdescribed by Brint et al (1988). Briefly, focal ischemia is produced byoccluding first the left common carotid artery and then the left middlecerebral artery just superior to the rhinal fissure. Followingocclusions, drugs are administered intravenously via jugular catheter.Twenty-four hours after MCA/common carotid artery occlusion, the animalsare sacrificed and their brains quickly removed. Coronal sections of 1mm thickness are cut using a vibratome and stained with2,3,5-triphenyl-2H-tetrazolium chloride (TTC) dye. Following staining,necrotic tissue is readily distinguished from the intact brain and thearea of infarcted cortex can be traced on an image analyzer. The infarctvolume for each section is quantified with an image analyzer, and thetotal infarct volume is calculated with a program that sums all intervalvolumes. See S. Brint et al. J. Cerebral Blood Flow 8:474-475 (1988).The statistical analysis of the difference between the volume ofischemic damage in the vehicle control and drug-treated animals isanalyzed by Student's t-test. The results are expressed as the percent(%) change in infarct volume and are presented as the mean for animals.

Representative tests results for the compounds of the instant inventionin the rat middle cerebral artery test are illustrated by the compoundof Example 18 which was found to provide a -19% change in infarct volumewhen administered intraveneously at a dose of 10 mg/kg per hour over 4hours.

Rat Red Nucleus Test

The purpose of this test is to determine the effects of intravenouslyadministered is glycine antagonists on the NMDA- induced excitatoryresponse of red nucleus cells. HA-966 (racemic) and CGP 37849 arereference agents that have been shown to be active in this test (ID₅₀ sof 7.9 and 1.7 mg/kg iv, respectively).

The procedure for the red nucleus test is as follows. Rats areanesthetized with chloral hydrate (400 mg/kg ip) and the femoral vein iscatheterized for iv drug administration. Five-barrel micropipettes arestereotaxically positioned in the red nucleus. Typically, three to fourof the five barrels are filled as follows: the recording barrel with 2Mpotassium citrate. the current balancing barrel with 4M NaCl, the drugbarrel with 25 mM NMDA, and another drug barrel with 2.5 mM quisqualicacid (QA is only used in selectivity studies). NMDA is iontophoreticallyapplied with an ejection current that is adjusted depending on thesensitivity of each individual red nucleus cell. The NMDA is cycled onand off (usually 30-60 sec. on and 60-120 sec. off) and the firing rateof the cell during each period is recorded. Once the baseline firingrate of the cell has been established, the test drug is administered iv.The inhibitory effect of the drug on the NMDA-induced excitatoryresponse of the red nucleus cell can then be both qualitatively andquantitatively evaluated from the recordings and the raw dataaccumulated and the results are expressed as an ID₅₀ value (The dose inmg/kg of the test drug which causes 50% inhibition).

Representative test results for the compounds of the instant inventionin the rat red nucleus test are illustrated by the compounds of Examples1(e), 8, 13, 17-19, 23(e), 26-28, 30, 32, 34, 36, 38-40, 42 and 47 whichwere found to possess ID₅₀ values in the range of about 3.0 mg/kg toabout 100 mg/kg. For example, the compounds of Examples 18, 27 and 28were found to possess ID₅₀ values of 3.5, 5.7 and 4.6 mg/kgrespectively.

The compounds of the invention are generally administered to patientswhich include, but are not limited to, mammals such as, for example,man. It will also be apparent to those skilled in the art that acompound according to the invention can be coadministered with othertherapeutic or prophylactic agents and/or medicaments that are notmedically incompatible therewith.

The compounds of the invention can be prepared for pharmaceutical use byconventional pharmaceutical procedures that are well known in the art;that is, by formulating a pharmaceutical composition which comprisescompounds of the invention or their pharmaceutically acceptable saltstogether with one or more pharmaceutically acceptable carriers,adjuvants, diluents or vehicles, for oral administration in solid orliquid form, parenteral administration, topical administration, rectaladministration, or aerosol inhalation administration, and the like.

Solid compositions for oral administration include compressed tablets,pills, powders and granules. In such solid compositions, the activecompound is admixed with at least one inert diluent such as starch,calcium carbonate, sucrose or lactose. These compositions may alsocontain additional substances other than inert diluents, e.g.,lubricating agents, such as magnesium stearate, talc and the like.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirscontaining inert diluents commonly used in the art, such was water andliquid paraffin. Besides inert diluents such compositions may alsocontain adjuvants, such as wetting and suspending agents, andsweetening, flavoring, perfuming and preserving agents. According to theinvention, the compounds for oral administration also include capsulesof absorbable material, such as gelatin, containing said activecomponent with or without the addition of diluents or excipients.

Preparations according to the invention for parenteral administrationinclude sterile aqueous, aqueous-organic, and organic solutions,suspensions and emulsions. Examples of organic solvents or suspendingmedia are propylene glycol, polyethylene glycol, vegetable oils such asolive oil and injectable organic esters such as ethyl oleate. Thesecompositions can also contain adjuvants such as stabilizing, preserving,wetting, emulsifying and dispersing agents.

Preparations according to the invention for topical administration oraerosol inhalation administration include dissolving or suspending acompound of the invention in a pharmaceutically acceptable vehicle suchas water, aqueous alcohol, glycol, oil solution or oil-water emulsion,and the like.

Preparations according to the invention for rectal administrationinclude suppositories prepared by using suitable carriers, e.g., cacaobutter, hardened oils, glycerides or saturated fatty acids and the like.

If desired, the compounds of the invention can further be incorporatedinto slow release or targeted delivery systems such as polymer matrices,liposomes, and microspheres.

The percentage of active component in such compositions may be varied sothat a suitable dosage is obtained. The dosage administered to aparticular patient is variable depending upon the clinician's judgmentusing as criteria: The route of administration, the duration oftreatment, the size and physical condition of the patient, the potencyof the active component and the patient's response thereto. An effectivedosage amount of the active component can thus readily be determined bythe clinician after a consideration of all criteria and using his bestjudgment on the patient's behalf. In general, a compound of the instantinvention is administered at a dose in the range of about 0.01 to about100 mg/kg body weight.

What is claimed is:
 1. A compound of the formula I ##STR27## wherein: Xis O or S;R¹, R², R³ and R⁴ are independently hydrogen,perfluorolower-alkyl, halogen, nitro or cyano; C together with thecarbon atoms to which it is attached forms a 5-membered aromaticheterocycle of the formula ##STR28## or tautomers thereof, wherein: R isselected from cyano, formyl, phenylcarbonyl, phenyl,lower-alkylcarbonyl, perfluorolower-alkyl,lower-alkoxy-carbonyl-lower-alkyl, carboxy-lower-alkyl, andphenyl-lower-alkylcarbonyl; wherein said phenyl, phenyl-lower-alkyl,phenyl-lower-alkynyl, phenyl-lower-alkylamino, phenylcarbonyl orphenyl-lower-alkylcarbonyl groups may optionally be substituted on thephenyl group thereof by one to three substituents, the same ordifferent, selected from the group consisting of lower-alkyl,lower-alkoxy, halogen, hydroxy and trifluoromethyl; or R is --C(O)OR⁵,where R⁵ is selected from hydrogen, lower-alkyl, lower-alkenyl,lower-alkynyl, cycloalkyl-lower-alkyl, phenyl, phenyl-lower-alkyl,phenyl-lower-alkynyl, lower-alkylthio-lower-alkyl, halo-lower-alkyl,trifluoromethyl-lower-alkyl, lower-alkoxy-lower-alkyl,hydroxy-lower-alkyl, lower-alkylamino, cycloalkylamino, andphenyl-lower-alkylamino; or R is --C(O)NR⁶ R⁷, where R⁶ and R⁷ areindependently selected from hydrogen, phenyl, phenyl-lower-alkyl,lower-alkoxy-lower-alkyl, hydroxylower-alkyl, lower-alkyl, lower-alkoxy,hydroxy, and cycloalkyl, or R⁶ and R⁷ together with the nitropen atom towhich they are attached form a 5- or 6-membered non-aromatic heterocycleselected from morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl andthiomorpholinyl: or a pharmaceutically-acceptable acid-addition salt ofbasic members thereof; or a pharmaceutically-acceptable base-additionsalt of acidic members thereof.
 2. A compound according to claim 1wherein R is cyano, --C(O)OR⁵ (wherein R⁵ is hydrogen, lower-alkyl,lower-alkenyl, lower-alkynyl, cycloalkyl-lower-alkyl, phenyl,phenyl-lower-alkyl, phenyl-lower-alkynyl, lower-alkylthiolower-alkyl,halo-lower-alkyl, trifluoromethyl-lower-alkyl, lower-alkyl-amino,cycloalkylamino, or phenyl-lower-alkylamino), --C(O)NR⁶ R⁷ (wherein R⁶and R⁷ are independently hydrogen, phenyl, phenyl-lower-alkyl,lower-alkoxy-lower-alkyl, lower-alkyl, lower-alkoxy, hydroxy orcycloalkyl, or R⁶ and R⁷ together with the nitrogen atom to which theyare attached form a morpholinyl group), formyl, phenylcarbonyl, phenyl,lower-alkylcarbonyl, perfluorolower-alkyl,lower-alkoxycarbonyl-lower-alkyl, or carboxy-lower-alkyl; wherein saidphenyl, phenyl-lower-alkyl, phenyl-lower-alkynyl,phenyl-lower-alkylamino or phenyl-carbonyl groups may optionally besubstituted on the phenyl group thereof by one substituent selected fromthe group consisting of lower-alkyl, lower-alkoxy, halogen, hydroxy andtrifluoromethyl.
 3. A compound according to claim 2 wherein R is cyano,--C(O)OR⁵ (wherein R⁵ is hydrogen, lower-alkyl, lower-alkenyl,lower-alkynyl, cycloalkyl-lower-alkyl, phenyl, phenyl-lower-alkyl,phenyl-lower-alkynyl, lower-alkylthio-lower-alkyl, halo-lower-alkyl,trifluoromethyl-lower-alkyl, lower-alkyl-amino, cycloalkylamino, orphenyl-lower-alkylamino), --C(O)NR⁶ R⁷ (wherein R⁶ and R⁷ areindependently hydrogen, phenyl, phenyl-lower-alkyl,lower-alkoxy-lower-alkyl, lower-alkyl, lower-alkoxy, or hydroxy, or R⁶and R⁷ together with the nitrogen atom to which they are attached form amorpholinyl group), formyl, phenylcarbonyl, phenyl,perfluorolower-alkyl, lower-alkoxycarbonyl-lower-alkyl, orcarboxy-lower-alkyl.
 4. A compound according to claim 3 wherein R¹, R²,R³ and R⁴ are independently hydrogen or halogen.
 5. A compound accordingto claim 4 wherein R is cyano, --C(O)OR⁵ (wherein R⁵ is hydrogen,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,2-propenyl, 3-butenyl, 1-methyl-3-butenyl, 3-methyl-3-butenyl,4-pentenyl, 3-butynyl, cyclopropylmethyl, phenyl, phenylmethyl,phenylethyl, phenylpropyl, 3-phenyl-2-propynyl, methylthioethyl,methylthiopropyl, chloroethyl, chloropropyl, 2,2,2-trifluoroethyl,isopropylamino, cyclohexylamino, tert-butyl-amino, phenylmethylamino),--C(O)NR⁶ R⁷ (wherein R⁶ and R⁷ are independently hydrogen,phenylmethyl, phenyl, methoxyethyl, ethoxyethyl, propyl, methyl,methoxy, or hydroxy, or R⁶ and R⁷ together with the nitrogen atom towhich they are attached form a morpholinyl group), formyl,phenylcarbonyl, phenyl, trifluoromethyl, tert-butoxycarbonylmethyl orcarboxymethyl.
 6. A compound according to claim 5 wherein one of R¹, R²,R³ or R⁴ is chloro and the others are hydrogen.
 7. A compound accordingto claim 5 selected from the group consistingof:7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,7-chloro-3-cyanopyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,7-chloro-3-trifluoromethylpyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,3-methoxycarbonyl-7-chloropyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,3-propoxycarbonyl-7-chloropyrazolo[3,4-c][1]benzepine-4,10(1H,9H)-dione,7-chloro-3-(2-propenyloxycarbonyl)pyrazolo[3,4-c][1]benzazepin-4,10(1H,9H)-dione,7-chloro-3-(isopropoxycarbonyl)pyrazolo[3,4-][1]-benzazepine-4,10(1H,9H)-dione,3-butoxycarbonyl-7-chloropyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,3-(3-butenyloxycarbonyl)-7-chloropyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,and3-(3-butynyloxycarbonyl)-7-chloropyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione;ora pharmaceutically acceptable salt thereof.
 8. A method for thetreatment of neurological disorders which comprises administering to apatient in need of such treatment an effective amount of a compound ofthe Formula I ##STR29## wherein: X is O or S;R¹, R², R ³ and R⁴ areindependently hydrogen, perfluorolower-alkyl, halogen, nitro or cyano;and C together with the carbon atoms to which it is attached forms a5-membered aromatic heterocycle selected from the group consisting of:##STR30## or tautomers thereof, wherein R is cyano, --C(O)OR⁵ (whereinR⁵ is hydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl,cvcloalkyl-lower-alkyl, phenyl, phenyl-lower-alkyl,phenyl-lower-alkynyl, lower-alkylthio-lower-alkyl, halo-lower-alkyl,trifluoromethyl-lower-alkyl, lower-alkoxy-lower-alkyl,hydroxy-lower-alkyl, lower-alkylamino, cycloalkylamino, orphenyl-lower-alkylamino), --C(O)NR⁶ R⁷ (wherein R⁶ and R⁷ areindependently hydrogen, phenyl, phenyl-lower-alkyllower-alkoxy-lower-alkyl, hydroxylower-alkyl, lower-alkyl, lower-alkoxy,hydroxy, or cycloalkyl, or R⁶ and R⁷ together with the nitrogen atom towhich they are attached form a 5- or 6-membered non-aromatic heterocycleselected from the group consisting of morpholinyl, piperidinyl,piperazinyl, pyrrolidinyl and thiomorpholinyl), formyl, phenylcarbonyl,phenyl, lower-alkylcarbonyl, perfluorolower-alkyl,lower-alkoxycarbonyl-lower-alkyl, carboxy-lower-alkyl, orphenyl-lower-alkylcarbonyl; wherein said phenyl, phenyl-lower-alkyl,phenyl-lower-alkynyl, phenyl-lower- alkylamino, phenylcarbonyl orphenyl-lower-alkylcarbonyl groups may optionally be substituted on thephenyl group thereof by one to three substituents, the same ordifferent, selected from the group consisting of lower-alkyl,lower-alkoxy, halogen, hydroxy and trifluoromethyl; or apharmaceutically acceptable acid-addition salt of basic members thereof,or a pharmaceutically acceptable base-addition salt of acidic membersthereof.
 9. A method according to claim 8 wherein C together with thecarbon atoms to which it is attached forms a 5-membered aromaticheterocycle of the formula ##STR31## or tautomers thereof.
 10. A methodaccording to claim 9 wherein R is cyano, --C(O)OR⁵ (wherein R⁵ ishydrogen, lower-alkyl, lower-alkenyl, lower-alkynyl,cycloalkyl-lower-alkyl, phenyl, phenyl-lower-alkyl,phenyl-lower-alkynyl, lower-alkylthiolower-alkyl, halo-lower-alkyl,trifluoromethyl-lower-alkyl, lower-alkylamino, cycloalkylamino, orphenyl-lower-alkylamino), --C(O)NR⁶ R⁷ (wherein R⁶ and R⁷ areindependently hydrogen, phenyl, phenyl-lower-alkyl,lower-alkoxy-lower-alkyl, lower-alkyl lower-alkoxy, hydroxy orcycloalkyl, or R⁶ and R⁷ together with the nitrogen atom to which theyare attached form a morpholinyl group), formyl, phenylcarbonyl, phenyl,lower-alkyl-carbonyl, perfluorolower-alkyl,lower-alkoxycarbonyl-lower-alkyl, or carboxy-lower-alkyl; wherein saidphenyl, phenyl-lower-alkyl, phenyl-lower-alkynyl,phenyl-lower-alkylamino or phenylcarbonyl groups may optionally besubstituted on the phenyl group thereof by one substituent selected fromthe group consisting of lower-alkyl, lower-alkoxy, halogen, hydroxy andtrifluoromethyl.
 11. A method according to claim 10 wherein R is cyano,--C(O)OR⁵ (wherein R⁵ is hydrogen, lower-alkyl, lower-alkenyl,lower-alkynyl, cycloalkyl-lower-alkyl, phenyl, phenyl-lower-alkyl,phenyl-lower-alkynyl, lower-alkyl-thiolower-alkyl, halo-lower-alkyl,trifluoromethyl-lower-alkyl, lower-alkylamino, cycloalkylarnino, orphenyl-lower-alkylamino), --C(O)NR⁶ R⁷ (wherein R⁶ and R⁷ areindependently hydrogen, phenyl, phenyl-lower-alkyl,lower-alkoxy-lower-alkyl, lower-alkyl, lower-alkoxy, or hydroxy, or R⁶and R⁷ together with the nitrogen atom to which they are attached form amorpholinyl group), formyl, phenylcarbonyl, phenyl,perfluorolower-alkyl, lower-alkoxycarbonyl-lower-alkyl, orcarboxy-lower-alkyl.
 12. A method according to claim 11 wherein R¹, R²,R³ and R⁴ are independently hydrogen or halogen.
 13. A method accordingto claim 12 wherein R is cyano, --C(O)OR⁵ (wherein R⁵ is hydrogen,methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl,2-propenyl, 3-butenyl, 1-methyl-3-butenyl, 3-methyl-3-butenyl,4-pentenyl, 3-butynyl, cyclopropylmethyl, phenyl, phenylmethyl,phenylethyl, phenylpropyl, 3-phenyl-2-propynyl, methylthioethyl,methylthiopropyl, chloroethyl, chloropropyl, 2,2,2-trifluoroethyl,isopropylamino, cyclohexylanmino, tert-butylamino, phenylmethylamino),--C(O)NR⁶ R⁷ (wherein R⁶ and R⁷ are independently hydrogen,phenylmethyl, phenyl, methoxyethyl, ethoxyethyl, propyl. methyl,methoxy, or hydroxy, or R⁶ and R⁷ together with the nitrogen atom towhich they are attached form a morpholinyl group), formyl,phenylcarbonyl, phenyl, trifluoromethyl, tert-butoxycarbonylmethyl orcarboxymethyl.
 14. A method according to claim 13 wherein one of R¹, R²,R³ or R⁴ is chloro and the others are hydrogen.
 15. A method accordingto claim 14 wherein the compound is selected from the group consistingof7-chloro-3-(carboxy)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,7-chloro-3-cyanopyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,7-chloro-3-trifluoromethylpyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,3-methoxycarbonyl-7-chloropyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,7-chloro-3-(ethoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,3-propoxycarbonyl-7-chloropyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,7-chloro-3-(2-propenyloxycarbonyl)pyrazolo[3,4-c]1]benzazepine-4,10(1H,9H)-dione,7-chloro-3-(isopropoxycarbonyl)pyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,3-butoxycarbonyl-7-chloropyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,3-(3-butenyloxycarbonyl)-7-chloropyrazolo[3,4-c][1]benzazepine-4,10(1H,9H)-dione,and3-(3-butynyloxycarbonyl)-7-chloropyrazolo[3,4-c[1]benzazepine-4,10(1H,9H)-dione;ora pharmaceutically acceptable salt thereof.
 16. A method according toclaim 8 wherein C together with the carbon atoms to which it is attachedforms a 5-membered aromatic heterocycle of the formula ##STR32## ortautomers thereof.
 17. A method according to claim 16 wherein R¹, R², R³and R⁴ are independently hydrogen or halogen.
 18. A method according toclaim 17 wherein one of R¹, R², R³ or R⁴ is chloro and the others arehydrogen.
 19. A method according to claim 18 wherein the compound isselected from the group consistingof:7-chloro-1,2,3-triazolo[4,5-c][1]benzazepine-4,10(1H,9H)-dione;6-chloro-1,2,3-triazolo[4,5-c]1]benzazepine-4,10(1H,9H)-dione; and5-chloro-1,2,3-triazolo[4,5-c][1]benzazepine-4,10(1H,9H)-dione;or apharmaceutically acceptable salt thereof.
 20. A method according toclaim 8 wherein said neurological disorder is stroke.
 21. Apharmaceutical composition which comprises a compound according to claim1, together with a pharmaceutically acceptable carrier, adjuvant,diluent or vehicle.
 22. A pharmaceutical composition which comprises acompound according to anyone of claims 1-7 together with apharmaceutically acceptable carrier, adjuvant, diluent or vehicle.
 23. Aprocess for preparing a compound according to claim 1 whichcomprises:(1) treating a compound of the Formula II ##STR33## wherein R'is lower-alkyl, with an ammonium salt, 2-hydroxy-pyridine, or a base toprepare a corresponding compound of the formula I wherein C is apyrazole ring.